Overfeeding polyunsaturated fat compared with saturated fat does not differentially influence lean tissue accumulation in individuals with overweight: a randomized controlled trial.

BACKGROUND: Fatty acids may influence lean tissue volume and skeletal muscle function. We previously reported in young lean participants that overfeeding PUFA compared with SFA induced greater lean tissue accumulation despite similar weight gain. OBJECTIVES: In a double-blind randomized controlled trial, we aimed to investigate if the differential effects of overfeeding SFA and PUFA on lean tissue accumulation could be replicated in individuals with overweight and identify potential determinants. Further, using substitution models, we investigated associations between SFA and PUFA concentrations with lean tissue volume in a large population-based sample (UK Biobank). METHODS: Sixty-one males and females with overweight [BMI (kg/m2): 27.3 (interquartile range (IQR), 25.4-29.3); age: 43 (IQR, 36-48)] were overfed SFA (palm oil) or n-6 (ω-6) PUFA (sunflower oil) for 8 wk. Lean tissue was assessed by MRI. We had access to n = 13,849 participants with data on diet, covariates, and MRI measurements of lean tissue, as well as 9119 participants with data on circulating fatty acids in the UK Biobank. RESULTS: Body weight gain mean (SD) was similar in PUFA (2.01 ± 1.90 kg) and SFA (2.31 ± 1.38 kg) groups. Lean tissue increased to a similar extent [0.54 ± 0.93 L and 0.67 ± 1.21 L for PUFA and SFA groups, respectively, with a difference between groups of 0.07 (-0.21, 0.35)]. We observed no differential effects on circulating amino acids, myostatin, or IL-15 and no clear determinants of lean tissue accumulation. Similar nonsignificant results for SFA and PUFA were observed in UK Biobank, but circulating fatty acids demonstrated ambiguous and sex-dependent associations. CONCLUSIONS: Overfeeding SFA or PUFA does not differentially affect lean tissue accumulation during 8 wk in individuals with overweight. A lack of dietary fat type-specific effects on lean tissue is supported by specified substitution models in a large population-based cohort consuming their habitual diet. This trial was registered at clinicaltrials.gov identifier as NCT02211612.

Design, synthesis and validation of a new Crimped Head-Piece for DNA-Encoded libraries generation.

Codification of DNA Encoded Libraries (DELs) is critical for successful ligand identification of molecules that bind a protein of interest (POI). There are different encoding strategies that permit, for instance, the customization of a DEL for testing single or dual pharmacophores (single strand DNA) or for producing and screening large diversity libraries of small molecules (double strand DNA). Both approaches challenges, either from the synthetic and encoding point of view, or from the selection methodology to be utilized for the screening. The Head-Piece contains the DNA sequence that is attached to a chemical compound, allowing the encoding of each molecule with a unique DNA tag. Designing the Head-Piece for a DNA-encoded library involves careful consideration of several key aspects including DNA barcode identity, sequence length and attachment chemistry. Here we describe a double stranded DNA versatile Head-Piece that can be used for the generation of single or dual pharmacophore libraries, but also shows other advanced DEL functionalities, stability and enlarged encoding capacity.

Long non-coding RNA APDC plays important regulatory roles in metabolism of bone and adipose tissues.

The long noncoding RNA (lncR) ANRIL in the human genome is an established genetic risk factor for atherosclerosis, periodontitis, diabetes, and cancer. However, the regulatory role of lncR-ANRIL in bone and adipose tissue metabolism remains unclear. To elucidate the function of lncRNA ANRIL in a mouse model, we investigated its ortholog, AK148321 (referred to as lncR-APDC), located on chr4 of the mouse genome, which is hypothesized to have similar biological functions to ANRIL. We initially revealed that lncR-APDC in mouse bone marrow cells (BMSCs) and lncR-ANRIL in human osteoblasts (hFOBs) are both increased during early osteogenesis. Subsequently, we examined the osteogenesis, adipogenesis, osteoclastogenesis function with lncR-APDC deletion/overexpression cell models. In vivo, we compared the phenotypic differences in bone and adipose tissue between APDC-KO and wild-type mice. Our findings demonstrated that lncR-APDC deficiency impaired osteogenesis while promoting adipogenesis and osteoclastogenesis. Conversely, the overexpression of lncR-APDC stimulated osteogenesis, but impaired adipogenesis and osteoclastogenesis. Furthermore, KDM6B was downregulated with lncR-APDC deficiency and upregulated with overexpression. Through binding-site analysis, we identified miR-99a as a potential target of lncR-APDC. The results suggest that lncR-APDC exerts its osteogenic function via miR-99a/KDM6B/Hox pathways. Additionally, osteoclasto-osteogenic imbalance was mediated by lncR-APDC through MAPK/p38 and TLR4/MyD88 activation. These findings highlight the pivotal role of lncR-APDC as a key regulator in bone and fat tissue metabolism. It shows potential therapeutic for addressing imbalances in osteogenesis, adipogenesis, and osteoclastogenesis.

Reference genes for quantitative Arabidopsis single molecule RNA fluorescence in situ hybridization.

Subcellular mRNA quantities and spatial distributions are fundamental for driving gene regulatory programmes. Single molecule RNA fluorescence in situ hybridization (smFISH) uses fluorescent probes to label individual mRNA molecules, thereby facilitating both localization and quantitative studies. Validated reference mRNAs function as positive controls and are required for calibration. Here we present selection criteria for the first set of Arabidopsis smFISH reference genes. Following sequence and transcript data assessments, four mRNA probe sets were selected for imaging. Transcript counts per cell, correlations with cell size, and corrected fluorescence intensities were all calculated for comparison. In addition to validating reference probe sets, we present sample preparation steps that can retain green fluorescent protein fluorescence, thereby providing a method for simultaneous RNA and protein detection. In summary, our reference gene analyses, modified protocol, and simplified quantification method together provide a firm foundation for future quantitative single molecule RNA studies in Arabidopsis root apical meristem cells.

Anthropometric Measurements and Correlations to Glucometabolic and Cardiovascular Risk in Obese Patients Undergoing Gastric Bypass Surgery.

Abdominal obesity is associated with hypertension, increased fasting glucose, HbA1c, and cholesterol. Body mass index (BMI) is frequently used to measure and define obesity and as inclusion criteria for bariatric surgery. Sagittal abdominal diameter (SAD) has been suggested to predict the amount of visceral fat, metabolic traits, and cardiometabolic risk superior to BMI. The aim was to test whether SAD has stronger correlations to glucometabolic traits compared to BMI. One hundred and fifty-five (108 women, 47 men) morbidly obese patients undergoing bariatric surgery were evaluated before (baseline), 6 and 12 months after Roux-en-Y gastric bypass (RYGBP). BMI was reduced from 43.7 kg/m2 (baseline) to 31.3 kg/m2 (12 months) and SAD from 32.6 to 23.2 cm (both p<0.001). SAD correlated with CRP (p=0.04), fasting glucose (p=0.008), HbA1c (p=0.016), triglycerides (p=0.017), systolic blood pressure (p=0.032), and vitamin D (p=0.027). BMI correlated with CRP (p=0.006), triglycerides (p=0.016), vitamin D (p=0.002), and magnesium (p=0.037). Despite RYGBP surgery, vitamin D was significantly increased. Liver enzymes were significantly lowered after RYGBP and the change over time in SAD correlated with gamma-glutamyltransferase. SAD was superior to BMI to predict glucose disturbance and dyslipidemia implying increased use of SAD as it is cost effective and simple to perform in the clinic and could be of value when considering patients for bariatric surgery.

Abdominal Fat and Metabolic Health Markers but Not PNPLA3 Genotype Predicts Liver Fat Accumulation in Response to Excess Intake of Energy and Saturated Fat in Healthy Individuals.

Background: Saturated fat (SFA) has consistently been shown to increase liver fat, but the response appears variable at the individual level. Phenotypic and genotypic characteristics have been demonstrated to modify the hypercholesterolemic effect of SFA but it is unclear which characteristics that predict liver fat accumulation in response to a hypercaloric diet high in SFA. Objective: To identify predictors of liver fat accumulation in response to an increased intake of SFA. Design: We pooled our two previously conducted double-blind randomized trials (LIPOGAIN and LIPOGAIN-2, clinicaltrials.gov NCT01427140 and NCT02211612) and used data from the n = 49 metabolically healthy men (n = 32) and women (n = 17) randomized to a hypercaloric diet through addition of SFA-rich muffins for 7-8 weeks. Associations between clinical and metabolic variables at baseline and changes in liver fat during the intervention were analyzed using Spearman rank correlation. Linear regression was used to generate a prediction model. Results: Liver fat increased by 33% (IQR 5.4-82.7%; P < 0.0001) in response to excess energy intake and this was not associated (r = 0.17, P = 0.23) with the increase in body weight (1.9 kg; IQR 1.1-2.9 kg). Liver fat accumulation was similar (P = 0.28) in carriers (33%, IQR 14-79%) and non-carriers (33%, IQR -11 to +87%) of the PNPLA3-I148M variant. Baseline visceral and liver fat content, as well as levels of the liver enzyme γ-glutamyl transferase (GT), were the strongest positive predictors of liver fat accumulation-in contrast, adiponectin and the fatty acid 17:0 in adipose tissue were the only negative predictors in univariate analyses. A regression model based on eight clinical and metabolic variables could explain 81% of the variation in liver fat accumulation. Conclusion: Our results suggest there exists a highly inter-individual variation in the accumulation of liver fat in metabolically healthy men and women, in response to an increased energy intake from SFA and carbohydrates that occurs over circa 2 months. This marked variability in liver fat accumulation could largely be predicted by a set of clinical (e.g., GT and BMI) and metabolic (e.g., fatty acids, HOMA-IR, and adiponectin) variables assessed at baseline.

The S-phase-induced lncRNA SUNO1 promotes cell proliferation by controlling YAP1/Hippo signaling pathway.

Cell cycle is a cellular process that is subject to stringent control. In contrast to the wealth of knowledge of proteins controlling the cell cycle, very little is known about the molecular role of lncRNAs (long noncoding RNAs) in cell-cycle progression. By performing genome-wide transcriptome analyses in cell-cycle-synchronized cells, we observed cell-cycle phase-specific induction of >2000 lncRNAs. Further, we demonstrate that an S-phase-upregulated lncRNA, SUNO1, facilitates cell-cycle progression by promoting YAP1-mediated gene expression. SUNO1 facilitates the cell-cycle-specific transcription of WTIP, a positive regulator of YAP1, by promoting the co-activator, DDX5-mediated stabilization of RNA polymerase II on chromatin. Finally, elevated SUNO1 levels are associated with poor cancer prognosis and tumorigenicity, implying its pro-survival role. Thus, we demonstrate the role of a S-phase up-regulated lncRNA in cell-cycle progression via modulating the expression of genes controlling cell proliferation.

Genome-wide association study of angioedema induced by angiotensin-converting enzyme inhibitor and angiotensin receptor blocker treatment.

Angioedema in the mouth or upper airways is a feared adverse reaction to angiotensin-converting enzyme inhibitor (ACEi) and angiotensin receptor blocker (ARB) treatment, which is used for hypertension, heart failure and diabetes complications. This candidate gene and genome-wide association study aimed to identify genetic variants predisposing to angioedema induced by these drugs. The discovery cohort consisted of 173 cases and 4890 controls recruited in Sweden. In the candidate gene analysis, ETV6, BDKRB2, MME, and PRKCQ were nominally associated with angioedema (p < 0.05), but did not pass Bonferroni correction for multiple testing (p < 2.89 × 10-5). In the genome-wide analysis, intronic variants in the calcium-activated potassium channel subunit alpha-1 (KCNMA1) gene on chromosome 10 were significantly associated with angioedema (p < 5 × 10-8). Whilst the top KCNMA1 hit was not significant in the replication cohort (413 cases and 599 ACEi-exposed controls from the US and Northern Europe), a meta-analysis of the replication and discovery cohorts (in total 586 cases and 1944 ACEi-exposed controls) revealed that each variant allele increased the odds of experiencing angioedema 1.62 times (95% confidence interval 1.05-2.50, p = 0.030). Associated KCNMA1 variants are not known to be functional, but are in linkage disequilibrium with variants in transcription factor binding sites active in relevant tissues. In summary, our data suggest that common variation in KCNMA1 is associated with risk of angioedema induced by ACEi or ARB treatment. Future whole exome or genome sequencing studies will show whether rare variants in KCNMA1 or other genes contribute to the risk of ACEi- and ARB-induced angioedema.

Estrogen-induced transcription at individual alleles is independent of receptor level and active conformation but can be modulated by coactivators activity.

Steroid hormones are pivotal modulators of pathophysiological processes in many organs, where they interact with nuclear receptors to regulate gene transcription. However, our understanding of hormone action at the single cell level remains incomplete. Here, we focused on estrogen stimulation of the well-characterized GREB1 and MYC target genes that revealed large differences in cell-by-cell responses, and, more interestingly, between alleles within the same cell, both over time and hormone concentration. We specifically analyzed the role of receptor level and activity state during allele-by-allele regulation and found that neither receptor level nor activation status are the determinant of maximal hormonal response, indicating that additional pathways are potentially in place to modulate cell- and allele-specific responses. Interestingly, we found that a small molecule inhibitor of the arginine methyltransferases CARM1 and PRMT6 was able to increase, in a gene specific manner, the number of active alleles/cell before and after hormonal stimulation, suggesting that mechanisms do indeed exist to modulate hormone receptor responses at the single cell and allele level.

Energy restriction in obese women suggest linear reduction of hepatic fat content and time-dependent metabolic improvements.

Energy restriction reduces liver fat, improves hepatic insulin resistance and lipid metabolism. However, temporal data in which these metabolic improvements occur and their interplay is incomplete. By performing repeated MRI scans and blood analysis at day 0, 3, 7, 14 and 28 the temporal changes in liver fat and related metabolic factors were assessed at five times during a low-calorie diet (LCD, 800-1100 kcal/day) in ten obese non-diabetic women (BMI 41.7 ± 2.6 kg/m2) whereof 6 had NAFLD. Mean weight loss was 7.4 ± 1.2 kg (0.7 kg/day) and liver fat decreased by 51 ± 16%, resulting in only three subjects having NAFLD at day 28. Marked alteration of insulin, NEFA, ALT and 3-hydroxybuturate was evident 3 days after commencing LCD, whereas liver fat showed a moderate but a linear reduction across the 28 days. Other circulating-liver fat markers (e.g. triglycerides, adiponectin, stearoyl-CoA desaturase-1 index, fibroblast growth factor 21) demonstrated modest and variable changes. Marked elevations of NEFA, 3-hydroxybuturate and ALT concentrations occurred until day 14, likely reflecting increased tissue lipolysis, fat oxidation and upregulated hepatic fatty acid oxidation. In summary, these results suggest linear reduction in liver fat, time-specific changes in metabolic markers and insulin resistance in response to energy restriction.

Overeating Saturated Fat Promotes Fatty Liver and Ceramides Compared With Polyunsaturated Fat: A Randomized Trial.

CONTEXT: Saturated fatty acid (SFA) vs polyunsaturated fatty acid (PUFA) may promote nonalcoholic fatty liver disease by yet unclear mechanisms. OBJECTIVE: To investigate if overeating SFA- and PUFA-enriched diets lead to differential liver fat accumulation in overweight and obese humans. DESIGN: Double-blind randomized trial (LIPOGAIN-2). Overfeeding SFA vs PUFA for 8 weeks, followed by 4 weeks of caloric restriction. SETTING: General community. PARTICIPANTS: Men and women who are overweight or have obesity (n = 61). INTERVENTION: Muffins, high in either palm (SFA) or sunflower oil (PUFA), were added to the habitual diet. MAIN OUTCOME MEASURES: Lean tissue mass (not reported here). Secondary and exploratory outcomes included liver and ectopic fat depots. RESULTS: By design, body weight gain was similar in SFA (2.31 ± 1.38 kg) and PUFA (2.01 ± 1.90 kg) groups, P = 0.50. SFA markedly induced liver fat content (50% relative increase) along with liver enzymes and atherogenic serum lipids. In contrast, despite similar weight gain, PUFA did not increase liver fat or liver enzymes or cause any adverse effects on blood lipids. SFA had no differential effect on the accumulation of visceral fat, pancreas fat, or total body fat compared with PUFA. SFA consistently increased, whereas PUFA reduced circulating ceramides, changes that were moderately associated with liver fat changes and proposed markers of hepatic lipogenesis. The adverse metabolic effects of SFA were reversed by calorie restriction. CONCLUSIONS: SFA markedly induces liver fat and serum ceramides, whereas dietary PUFA prevents liver fat accumulation and reduces ceramides and hyperlipidemia during excess energy intake and weight gain in overweight individuals.

Increased circulating magnesium concentrations after Roux-en-Y gastric bypass surgery in patients with type 2 diabetes.

BACKGROUND: Low circulating magnesium concentrations predict cardiovascular and all-cause mortality in patients with type 2 diabetes (T2D). Epidemiologic and clinical studies have indicated lower extra- and intracellular magnesium concentrations in patients with diabetes. OBJECTIVE: We aimed to describe alterations, if any, in circulating magnesium concentrations after laparoscopic Roux-en-Y gastric bypass surgery (LRYGB) in patients with obesity and T2D. SETTING: Outpatient clinic of obesity and central hospital. METHODS: Retrospective analysis of 1-year outcome of plasma magnesium (p-Mg) and glucometabolic status in all consecutive patients who underwent primary LRYGBP and who completed the follow-up visits, including biochemical test panels 6 and 12 months after surgery. RESULTS: LRYGBP and complete follow-up visits were performed in 51 patients with T2D and 86 patients without T2D. All patients were given similar dietary advice and multivitamin and mineral supplementation after surgery. Before RYGB, the patients with T2D showed lower p-Mg compared with patients without T2D (.79 ± .06 mM and .82 ± .05 mM, respectively, P<.01). P-Mg was inversely correlated to fasting blood glucose and glycosylated hemoglobin levels. After surgery, mean p-Mg increased by 5.2% in the group with T2D compared with 1.4% in the patients without T2D (P<.01), ending at an equal level of .83 mM. The alterations in p-Mg were inversely related to the changes in fasting glucose and glycosylated hemoglobin concentrations. CONCLUSION: The lowered p-Mg associated with impaired glucometabolic status in patients with T2D was increased after LRYGBP, reaching similar concentrations as in patients without T2D.

Full-length mRNA sequencing uncovers a widespread coupling between transcription initiation and mRNA processing.

BACKGROUND: The multifaceted control of gene expression requires tight coordination of regulatory mechanisms at transcriptional and post-transcriptional level. Here, we studied the interdependence of transcription initiation, splicing and polyadenylation events on single mRNA molecules by full-length mRNA sequencing. RESULTS: In MCF-7 breast cancer cells, we find 2700 genes with interdependent alternative transcription initiation, splicing and polyadenylation events, both in proximal and distant parts of mRNA molecules, including examples of coupling between transcription start sites and polyadenylation sites. The analysis of three human primary tissues (brain, heart and liver) reveals similar patterns of interdependency between transcription initiation and mRNA processing events. We predict thousands of novel open reading frames from full-length mRNA sequences and obtained evidence for their translation by shotgun proteomics. The mapping database rescues 358 previously unassigned peptides and improves the assignment of others. By recognizing sample-specific amino-acid changes and novel splicing patterns, full-length mRNA sequencing improves proteogenomics analysis of MCF-7 cells. CONCLUSIONS: Our findings demonstrate that our understanding of transcriptome complexity is far from complete and provides a basis to reveal largely unresolved mechanisms that coordinate transcription initiation and mRNA processing.

Platelet Counts and Liver Enzymes After Gastric Bypass Surgery.

BACKGROUND: Obesity is associated with chronic inflammation, liver steatosis and increased liver enzymes such as gamma-glutamyltransferase (GGT) and alanine aminotransferase (ALT), markers for non-alcoholic fatty liver disease (NAFLD) and liver fat content. Increased platelet counts (PCs) are a biomarker reflecting inflammation and the degree of fibrosis in NAFLD. We investigated alterations in PCs, GGT, ALT, C-reactive protein (CRP) and ferritin after Roux-en-Y gastric bypass (RYGBP). METHODS: One hundred twenty-four morbidly obese non-diabetic patients were evaluated before (baseline) and 12 months after (follow-up) RYGBP. RESULTS: Body mass index (BMI) was reduced from 43.5 kg/m2 (baseline) to 31.1 kg/m2 (follow-up), and p < 0.001 and weight declined from 126.2 to 89.0 kg. PCs decreased from 303 × 109 to 260 × 109/l, p < 0.001. GGT was reduced from 0.63 to 0.38 µkat/l, p < 0.001. ALT decreased from 0.69 to 0.59 µkat/l, p = 0.006. CRP was lowered from 7.3 to 5.4 mg/l p < 0.001 and ferritin from 106 to 84 µg/l p < 0.001. The alterations in PCs correlated with the changes in CRP (r = 0.38, p = 0.001), BMI (r = 0.25, p = 0.012), weight (r = 0.24, p = 0.015) and inversely correlated with ferritin (r = 21, p = 0.036). CONCLUSIONS: PCs, GGT and ALT (markers for NAFLD), and CRP and ferritin (markers for inflammation) decreased in morbidly obese after RYGBP. The decrease in PCs correlated with alterations in CRP, BMI, weight and ferritin. The lowering of liver enzymes may reflect a lowered liver fat content and decreased general inflammation.

Influence of patient position and other inherent factors on image quality in two different cone beam computed tomography (CBCT) devices.

OBJECTIVES: The aim of this in vitro study was to evaluate how a deviation from the horizontal plane, affects the image quality in two different CBCT-devices. METHODS: A phantom head SK150 (RANDO, The Phantom Laboratory, Salem, NY, USA) was examined in two CBCT-units: Accuitomo 80 and Veraviewepocs 3D R100 (J. Morita Mfg. Corp. Kyoto, Japan). The phantom head was placed with the hard palate parallel to the horizontal plane and tilted 20 ° backwards. Exposures were performed with different field of views (FOVs), voxel sizes, slice thicknesses and exposure settings. Effective dose was calculated using PCXMC 2.0 (STUK, Helsinki, Finland). Image quality was assessed using contrast-to-noise-ratio (CNR). Region of interest (ROI) was set at three different levels of the mandibular bone and soft tissue, uni- and bilaterally in small and large FOVs, respectively. CNR values were calculated by CT-value and standard deviation for each ROI. Factor analysis was used to analyze the material. RESULTS: Tilting the phantom head backwards rendered significantly higher mean CNR values regardless of FOV. The effective dose was lower in small than in large FOVs and varied to a larger extent between CBCT-devices in large FOVs. CONCLUSIONS: Head position can affect the image quality. Tilting the head backward improved image quality in the mandibular region. However, if influenced by other variables e.g. motion artifacts in a clinical situation, remains to be further investigated. ADVANCES IN KNOWLEDGE: Image quality assessed using CNR values to investigate the influence of different patient positions and FOVs.

Do we need to measure vitamin B12 and magnesium in morbidly obese patients with type 2 diabetes mellitus?

OBJECTIVE: We aimed to investigate the prevalence of B12 deficiency in metformin-treated, morbidly obese, type 2 diabetes mellitus (T2DM) patients, compared to morbidly obese controls, as well as to evaluate the magnesium status. DESIGN: Retrospective cross-sectional analysis of plasma vitamin B12, plasma magnesium, glucometabolic status and clinical measurements in all consecutive morbidly obese patients was conducted during 1 year. SETTING: Outpatient Clinic of Obesity Care. SUBJECTS: One hundred forty-seven patients were evaluated: 107 morbidly obese controls and 40 metformin-treated, morbidly obese patients with T2DM. MAIN OUTCOME MEASURES: Circulating plasma concentrations of vitamin B12 (cobalamin), magnesium, clinical measurements and metformin medication. RESULTS: There were differences between the two groups regarding age, sagittal diameter, glucose parameters and magnesium concentrations. Longer diabetes duration was associated with lower magnesium. Metformin-treated T2DM patients had lower magnesium (0.76±0.07 mmol/L) than controls (0.82±0.07 mmol/L). A subgroup analysis of 26 non-metformin-treated T2DM patients showed a normal magnesium concentration compared to controls, that is, 0.81±0.06 mmol/L. We found no statistical difference in B12 concentrations between the two groups. CONCLUSION: To fully benefit from metformin medication, routine testing of B12 as well as magnesium in metformin-treated, morbidly obese patients should be performed, with consideration of substitution to avoid low levels.

Gene activation of SMN by selective disruption of lncRNA-mediated recruitment of PRC2 for the treatment of spinal muscular atrophy.

Spinal muscular atrophy (SMA) is a neurodegenerative disease characterized by progressive motor neuron loss and caused by mutations in SMN1 (Survival Motor Neuron 1). The disease severity inversely correlates with the copy number of SMN2, a duplicated gene that is nearly identical to SMN1. We have delineated a mechanism of transcriptional regulation in the SMN2 locus. A previously uncharacterized long noncoding RNA (lncRNA), SMN-antisense 1 (SMN-AS1), represses SMN2 expression by recruiting the Polycomb Repressive Complex 2 (PRC2) to its locus. Chemically modified oligonucleotides that disrupt the interaction between SMN-AS1 and PRC2 inhibit the recruitment of PRC2 and increase SMN2 expression in primary neuronal cultures. Our approach comprises a gene-up-regulation technology that leverages interactions between lncRNA and PRC2. Our data provide proof-of-concept that this technology can be used to treat disease caused by epigenetic silencing of specific loci.

Genetic variants associated with angiotensin-converting enzyme inhibitor-induced cough: a genome-wide association study in a Swedish population.

AIM: We conducted a genome-wide association study on angiotensin-converting enzyme inhibitor-induced cough and used our dataset to replicate candidate genes identified in previous studies. PATIENTS & METHODS: A total of 124 patients and 1345 treated controls were genotyped using Illumina arrays. The genome-wide significance level was set to p < 5 × 10-8. RESULTS: We identified nearly genome-wide significant associations in CLASP1, PDE11A, KCNMB2, TGFA, SLC38A6 and MMP16. The strongest association was with rs62151109 in CLASP1 (odds ratio: 3.97; p = 9.44 × 10-8). All top hits except two were located in intronic or noncoding DNA regions. None of the candidate genes were significantly associated in our study. CONCLUSION: Angiotensin-converting enzyme inhibitor-induced cough is potentially associated with genes that are independent of bradykinin pathways.

Comparison of Clinical Factors Between Patients With Angiotensin-Converting Enzyme Inhibitor-Induced Angioedema and Cough.

BACKGROUND: Angioedema is a rare and serious adverse drug reaction (ADR) to angiotensin-converting enzyme (ACE) inhibitor treatment. Dry cough is a common side effect of ACE inhibitors and has been identified as a possible risk factor for angioedema. OBJECTIVE: We compared characteristics between patients with ACE inhibitor-induced angioedema and cough with the aim of identifying risk factors that differ between these adverse events. METHODS: Data on patients with angioedema or cough induced by ACE inhibitors were collected from the Swedish database of spontaneously reported ADRs or from collaborating clinicians. Wilcoxon rank sum test, Fisher's exact test, and odds ratios (ORs) with 95% CIs were used to test for between-group differences. The significance threshold was set to P <0.00128 to correct for multiple comparisons. RESULTS: Clinical characteristics were compared between 168 patients with angioedema and 121 with cough only. Smoking and concomitant selective calcium channel blocker treatment were more frequent among patients with angioedema than cough: OR = 4.3, 95% CI = 2.1-8.9, P = 2.2 × 10-5, and OR = 3.7, 95% CI = 2.0-7.0, P = 1.7 × 10-5. Angioedema cases were seen more often in male patients (OR = 2.2, 95% CI = 1.4-3.6, P = 1.3 × 10-4) and had longer time to onset and higher doses than those with cough ( P = 3.2 × 10-10 and P = 2.6 × 10-4). A multiple model containing the variables smoking, concurrent calcium channel blocker treatment, male sex, and time to onset accounted for 26% of the variance between the groups. CONCLUSION: Smoking, comedication with selective calcium channel blockers, male sex, and longer treatment time were associated with ACE inhibitor-induced angioedema rather than cough.

Diabetes treatment and hypoglycaemic episodes in elderly patients at nursing homes in Uppsala County.

AIM: The aim of this study was to examine the situation for elderly patients with diabetes living in nursing homes with regard to diabetes treatment, clinical variables, and vascular complications associated with diabetes. A second aim was to evaluate if the patients were at risk of hypoglycaemia. METHODS: This was a cross-sectional study including diabetes patients from all 30 nursing homes in Uppsala County, Sweden. Current antidiabetic medications, HbA1c, hypoglycaemic events, and diabetes complications were registered from the medical records. The patients were stratified into a general group and divided into three groups according to HbA1c (<52, 52-73, and >73 mmol/mol). RESULTS: Of 1,350 individuals, 218 patients were identified with diabetes mellitus. The diabetes duration was 11.2 ± 9.4 years and their serum HbA1c concentration 56.0 ± 1.2 mmol/mol. Hypoglycaemic events were reported in 24% of the diabetic individuals, and 43.1% of them had HbA1c <52 mmol/mol (mean value 44.0 ± 1.1 mmol/mol). Of these, 36% were taking antidiabetic drugs. Another 35.8% of the patients had HbA1c values between 52-73 mmol/mol (mean value 60.0 ± 1.1 mmol/mol), and 82% of these patients were taking antidiabetic drugs. Almost 80% of the diabetic patients had either micro- or macrovascular complications, with diabetes duration as an association for both micro- or macrovascular complications and hypoglycaemic events. CONCLUSIONS: A reduction of the use of antidiabetic drugs with follow-up of HbA1c level should be considered, especially for multimorbid elderly patients with low HbA1c and hypoglycaemia.