Next-generation sequencing of the mitochondrial genome and association with IgA nephropathy in a renal transplant population

Kidneys are highly aerobic organs that are critically dependent on the normal functioning of mitochondria. Genetic variations disrupting mitochondrial function are associated with multifactorial disorders including kidney disease. This study sequenced the entire mitochondrial genome in a renal transplant cohort of 64 individuals, using next-generation sequencing, to evaluate the association of genetic variants with IgA nephropathy and end-stage renal disease (ESRD, n = 100).

Comparison of Microbiomes from Different Niches of Upper and Lower Airways in Children and Adolescents with Cystic Fibrosis

Changes in the airway microbiome may be important in the pathophysiology of chronic lung disease in patients with cystic fibrosis. However, little is known about the microbiome in early cystic fibrosis lung disease and the relationship between the microbiomes from different niches in the upper and lower airways. Therefore, in this cross-sectional study, we examined the relationship between the microbiome in the upper (nose and throat) and lower (sputum) airways from children with cystic fibrosis using next generation sequencing. Our results demonstrate a significant difference in both α and β-diversity between the nose and the two other sampling sites. The nasal microbiome was characterized by a polymicrobial community while the throat and sputum communities were less diverse and dominated by a few operational taxonomic units. Moreover, sputum and throat microbiomes were closely related especially in patients with clinically stable lung disease. There was a high inter-individual variability in sputum samples primarily due to a decrease in evenness linked to increased abundance of potential respiratory pathogens such as Pseudomonas aeruginosa. Patients with chronic Pseudomonas aeruginosa infection exhibited a less diverse sputum microbiome. A high concordance was found between pediatric and adult sputum microbiomes except that Burkholderia was only observed in the adult cohort. These results indicate that an adult-like lower airways microbiome is established early in life and that throat swabs may be a good surrogate in clinically stable children with cystic fibrosis without chronic Pseudomonas aeruginosa infection in whom sputum sampling is often not feasible.

Antimicrobial resistance in the respiratory microbiota of people with cystic fibrosis

Cystic fibrosis is characterised by chronic polymicrobial infection and inflammation in the airways of patients. Antibiotic treatment regimens, targeting recognised pathogens, have substantially contributed to increased life expectancy of patients with this disease. Although the emergence of antimicrobial resistance and selection of highly antibiotic-resistant bacterial strains is of major concern, the clinical relevance in cystic fibrosis is yet to be defined. Resistance has been identified in recognised cystic fibrosis pathogens and in other bacteria (eg, Prevotella and Streptococcus spp) detected in the airway microbiota, but their role in the pathophysiology of infection and inflammation in chronic lung disease is unclear. Increased antibiotic resistance in cystic fibrosis might be attributed to a range of complex factors including horizontal gene transfer, hypoxia, and biofilm formation. Strategies to manage antimicrobial resistance consist of new antibiotics or localised delivery of antimicrobial agents, iron sequestration, inhibition of quorum-sensing, and resistome analysis. Determination of the contributions of every bacterial species to lung health or disease in cystic fibrosis might also have an important role in the management of antibiotic resistance. 

IHG-1 increases mitochondrial fusion and bioenergetic function

Induced in high glucose-1 (IHG-1) is a conserved mitochondrial protein associated with diabetic nephropathy (DN) that amplifies profibrotic transforming growth factor (TGF)-β1 signaling and increases mitochondrial biogenesis. Here we report that inhibition of endogenous IHG-1 expression results in reduced mitochondrial respiratory capacity, ATP production, and mitochondrial fusion. Conversely, overexpression of IHG-1 leads to increased mitochondrial fusion and also protects cells from reactive oxygen species-induced apoptosis. IHG-1 forms complexes with known mediators of mitochondrial fusion-mitofusins (Mfns) 1 and 2-and enhances the GTP-binding capacity of Mfn2, suggesting that IHG-1 acts as a guanine nucleotide exchange factor. IHG-1 must be localized to mitochondria to interact with Mfn1 and Mfn2, and this interaction is necessary for increased IHG-1-mediated mitochondrial fusion. Together, these findings indicate that IHG-1 is a novel regulator of both mitochondrial dynamics and bioenergetic function and contributes to cell survival following oxidant stress. We propose that in diabetic kidney disease increased IHG-1 expression protects cell viability and enhances the actions of TGF-β, leading to renal proximal tubule dedifferentiation, an important event in the pathogenesis of this devastating condition.

Common causes and current guidelines

Chronic cough is a common and disabling symptom. Recent guidelines have attempted to provide direction in the clinical management of cough in both primary and secondary care. They have also provided a critical review of the available literature and identified gaps in current knowledge. Despite this they have been criticized for a reliance on a low quality evidence base. In this review, we summarize the current consensus on the clinical management of chronic cough and attempt to rationalize this based on recent evidence. We have also provided an overview of the likely pathophysiological mechanisms responsible for cough and highlighted areas, where knowledge deficits exist and suggest directions for future research. Such progress will be critical in the search for new and effective treatments for cough.

Randomized controlled trial assessing the effect of simvastatin in primary biliary cirrhosis

Background This study evaluated the effect of statins in Primary biliary cirrhosis (PBC) on endothelial function, anti-oxidant status and vascular compliance. Methods Primary biliary cirrhosis patients with hypercholesterolaemia were randomized to receive 20mg simvastatin or placebo in a single blind, randomized controlled trial. Body mass index, blood pressure, glucose, liver function, lipid profile, immunoglobulin levels, serological markers of endothelial function and anti-oxidant status were measured as well as vascular compliance, calculated from pulse wave analysis and velocity, at recruitment and again at 3, 6, 9 and 12months. Results Twenty-one PBC patients (F=20, mean age = 55) were randomized to simvastatin 20mg (n=11) or matched placebo (n=10). At completion of the trial, serum cholesterol levels in the simvastatin group were significantly lower compared with the placebo group (4.91mmol/L vs. 6.15mmol/L, P=0.01). Low-density lipoprotein (LDL) levels after 12months were also significantly lower in the simvastatin group (2.33mmol/L vs. 3.53mmol/L, P=0.01). After 12months of treatment, lipid hydroperoxides were lower (0.49mol/L vs. 0.59mol/L, P=0.10) while vitamin C levels were higher (80.54mol/L vs. 77.40mol/L, P=0.95) in the simvastatin group. Pulse wave velocity remained similar between treatment groups at 12months (8.45m/s vs. 8.80m/s, P=0.66). Only one patient discontinued medication owing to side effects. No deterioration in liver transaminases was noted in the simvastatin group. Conclusions Statin therapy in patients with PBC appears safe and effective towards overall reductions in total cholesterol and LDL levels. Our initial study suggests that simvastatin may also confer advantageous effects on endothelial function and antioxidant status.

The Impact of Multimedia Education on Uptake of Comprehensive Eye Examinations in Rural China: A Randomized, Controlled Trial

PURPOSE: To study the effect of multimedia education on acceptance of comprehensive eye examinations (CEEs), critical for detecting glaucoma and diabetic eye disease, among rural Chinese patients using a randomized, controlled design.
METHODS: Patients aged ≥40 years were recruited from 52 routine clinic sessions (26 intervention, 26 control) conducted at seven rural hospitals in Guangdong, China. Subjects answered demographic questionnaires, were tested on knowledge about CEEs and chronic eye disease, and were told the cost of examination (range US$0-8). At intervention sessions, subjects were cluster-randomized to view a 10-minute video on the value of CEEs and retested. Control subjects were not retested. Trial outcomes were acceptance of CEEs (primary outcome) and final knowledge scores (secondary outcome).
RESULTS: At baseline, >70% (p = 0.70) of both intervention (n = 241, 61.2 ± 12.3 years) and control (n = 218, 58.4 ± 11.7 years) subjects answered no knowledge questions correctly, but mean scores on the test (maximum 5 points) increased by 1.39 (standard deviation 0.12) points (p < 0.001) after viewing the video. Intervention (73.0%) and control (72.9%) subjects did not differ in acceptance of CEEs (p > 0.50). In mixed-effect logistic regression models, acceptance of CEEs was associated with availability of free CEEs (odds ratio 18.3, 95% confidence interval 1.32-253.0), but not group assignment or knowledge score. Acceptance was 97.5% (79/81) when free exams were offered.
CONCLUSIONS: Education increased knowledge about but not acceptance of CEEs, which was generally high. Making CEEs free could further increase acceptance.