Genetic evidence for a potential causal relationship between insomnia symptoms and suicidal behavior: a Mendelian randomization study

Insomnia and restless leg syndrome (RLS) are associated with increased risk for suicidal behavior (SB), which is often comorbid with mood or thought disorders; however, it is unclear whether these relationships are causal. We performed a two-sample Mendelian randomization study using summary-level genetic associations with insomnia symptoms and RLS against the outcomes of risk of major depressive disorder (MDD), bipolar disorder (BP), schizophrenia (SCZ), and SB. The inverse-variance weighted method was used in the main analysis. We performed replication and sensitivity analyses to examine the robustness of the results. We identified outcome cohorts for MDD (n = 170,756 cases/329,443 controls), BP (n = 20,352/31,358), SCZ (n = 69,369/236,642), SB-Cohort-2019 (n = 6569/14,996 all with MDD, BP or SCZ; and SB within individual disease categories), and SB-Cohort-2020 (n = 29,782/519,961). Genetically proxied liability to insomnia symptoms significantly associated with increased risk of MDD (odds ratio (OR) = 1.23, 95% confidence interval (CI) = 1.2–1.26, P = 1.37 × 10^–61), BP (OR = 1.15, 95% CI = 1.07–1.23, P = 5.11 × 10^–5), SB-Cohort-2019 (OR = 1.17, 95% CI = 1.07–1.27, P = 2.30 × 10^–4), SB-Cohort-2019 in depressed patients (OR = 1.34, 95% CI = 1.16–1.54, P = 5.97 × 10^–5), and SB-Cohort-2020 (OR = 1.24, 95% CI = 1.18–1.3, P = 1.47 × 10^–18). Genetically proxied liability to RLS did not significantly influence the risk of any of the outcomes (all corrected P > 0.05). Results were replicated for insomnia with MDD and SB in Mass General Brigham Biobank and were consistent in multiple lines of sensitivity analyses. In conclusion, human genetic evidence supports for the first time a potentially independent and causal effect of insomnia on SB and encourages further clinical investigation of treatment of insomnia for prevention or treatment of SB.Subject terms: Genetic markers, Risk factors, Psychiatric disorders     

Assessing the Causal Role of Sleep Traits on Glycated Hemoglobin: A Mendelian Randomization Study

OBJECTIVETo examine the effects of sleep traits on glycated hemoglobin (HbA_1c).RESEARCH DESIGN AND METHODSThis study triangulated evidence across multivariable regression (MVR) and one- (1SMR) and two-sample Mendelian randomization (2SMR) including sensitivity analyses on the effects of five self-reported sleep traits (i.e., insomnia symptoms [difficulty initiating or maintaining sleep], sleep duration, daytime sleepiness, napping, and chronotype) on HbA_1c (in SD units) in adults of European ancestry from the UK Biobank (for MVR and 1SMR analyses) (n = 336,999; mean [SD] age 57 [8] years; 54% female) and in the genome-wide association studies from the Meta-Analyses of Glucose and Insulin-Related Traits Consortium (MAGIC) (for 2SMR analysis) (n = 46,368; 53 [11] years; 52% female).RESULTSAcross MVR, 1SMR, 2SMR, and their sensitivity analyses, we found a higher frequency of insomnia symptoms (usually vs. sometimes or rarely/never) was associated with higher HbA_1c (MVR 0.05 SD units [95% CI 0.04–0.06]; 1SMR 0.52 [0.42–0.63]; 2SMR 0.24 [0.11–0.36]). Associations remained, but point estimates were somewhat attenuated after excluding participants with diabetes. For other sleep traits, there was less consistency across methods, with some but not all providing evidence of an effect.CONCLUSIONSOur results suggest that frequent insomnia symptoms cause higher HbA_1c levels and, by implication, that insomnia has a causal role in type 2 diabetes. These findings could have important implications for developing and evaluating strategies that improve sleep habits to reduce hyperglycemia and prevent diabetes.     

Biopsy proven acute interstitial nephritis after treatment with moxifloxacin

Background

Acute interstitial nephritis (AIN) is an important cause of reversible acute kidney injury. At least 70% of AIN is caused by various drugs, mainly penicillines and non-steroidal anti-inflammatory drugs. Quinolones are only rarely known to cause AIN and so far cases have been mainly described with older fluoroquinolones.

Case Presentation

Here we describe a case of biopsy proven interstitial nephritis after moxifloxacin treatment. The patient presented with fever, rigors and dialysis dependent acute kidney injury, just a few days after treatment of a respiratory tract infection with moxifloxacin. The renal biopsy revealed dense infiltrates mainly composed of eosinophils and severe interstitial edema. A course of oral prednisolone (1 mg/kg/day) was commenced and rapidly tapered to zero within three weeks. The renal function improved, and the patient was discharged with a creatinine of 107 μmol/l.

Conclusion

This case illustrates that pharmacovigilance is important to early detect rare side effects, such as AIN, even in drugs with a favourable risk/benefit ratio such as moxifloxacin.     

Hepatic cavernous hemangiomas: patterns of contrast enhancement on MR fluoroscopy imaging

PURPOSE: The purpose of this study was to assess the patterns of contrast enhancement of hepatic hemangiomas on gadolinium-enhanced MR fluoroscopy imaging prospectively. METHOD: Investigation was performed on a 0.3-T open MR unit. Gadolinium-enhanced MR fluoroscopy images were obtained in 24 patients with 28 hepatic hemangiomas. Each MR fluoroscopy image was obtained in 2 s and MR fluoroscopy lasted for 10-25 min for each investigation. RESULTS: Three patterns of contrast enhancement were observed in 24 patients on MR fluoroscopy images. Four small lesions were not detected on MR fluoroscopy images. Uniform enhancement was seen in nine lesions (29%), peripheral nodular enhancement progressing centripetally to uniform enhancement was seen in nine lesions (29%), and peripheral nodular enhancement with persistent central hypointensity was seen in six lesions (22%). CONCLUSION: Enhanced MR fluoroscopy technique could obtain dynamic images of hepatic hemangiomas. It can be suggested as a useful technique for the showing of enhancement of hepatic hemangiomas, keeping in mind its low sensitivity in the diagnosis of small hemangiomas.     

Soluble activin receptor type IIB decoy receptor differentially impacts murine osteogenesis imperfecta muscle function

Introduction: Osteogenesis imperfecta (OI) is characterized by skeletal fragility and muscle weakness. In this study we investigated the effects of soluble activin type IIB receptor (sActRIIB‐mFc) on muscle mass and function in 2 distinct mouse models of OI: osteogenesis imperfecta murine (oim) and +/G610C. Methods: Wild‐type (WT), +/G610C, and oim/oim mice were treated from 2 to 4 months of age with Tris‐buffered saline (vehicle) or sActRIIB‐mFc and their hindlimb muscles evaluated for mass, morphology, and contractile function. Results: sActRIIB‐mFc‐treated WT, +/G610C, and oim/oim mice had increased hindlimb muscle weights and myofiber cross‐sectional area compared with vehicle‐treated counterparts. sActRIIB‐mFc‐treated oim/oim mice also exhibited increased contractile function relative to vehicle‐treated counterparts. Discussion: Blocking endogenous ActRIIB was effective at increasing muscle size in mouse models of OI, and increasing contractile function in oim/oim mice. ActRIIB inhibitors may provide a potential mutation‐specific therapeutic option for compromised muscle function in OI. Muscle Nerve 57 : 294–304, 2018     

Inhibition of myeloperoxidase activity by the alkaloids of Peganum harmala L. (Zygophyllaceae)

Ethnopharmacological relevance

Seeds and aerial parts of Peganum harmala L. are widely used in Algeria as anti-inflammatory remedies. Evaluation of Peganum harmala total alkaloids extracts and pure β-carboline compounds as an anti-inflammatory treatment by the inhibition of an enzyme key of inflammatory, myeloperoxidase (MPO) and HPLC quantification of the alkaloids from the different parts of plant.

Materials and methods

MPO inhibition was tested using taurine chloramine test. The inhibition of LDL oxidation induced by MPO was carried out. The molecular docking analysis of Peganum harmala alkaloids on MPO was performed using the Glide XP docking protocol and scoring function and the redox potential of alkaloids was determined using an Epsilon potentiostat. The concentration of harmala alkaloids was determined using HPLC analysis.

Results

The HPLC profiling of the active total alkaloids indicates that β-carboline e.g. harmine, harmaline, harmane, harmol and harmalol are major components. As β-carbolines resemble tryptamine, of which derivatives are efficient inhibitors of MPO, the harmala alkaloids were tested for their activity on this enzyme. Total alkaloids of the seeds and of the aerial parts strongly inhibited MPO at 20 µg/mL (97±5% and 43±4%, respectively) whereas, at the same concentration, those of the roots showed very low inhibition (15±6%). Harmine, harmaline and harmane demonstrated a significant inhibition of MPO at IC₅₀ of 0.26, 0.08 and 0.72 µM respectively. These alkaloids exerted a similar inhibition effects on MPO-induced LDL oxidation. Molecular docking analysis of Peganum harmala alkaloids on MPO showed that all active Peganum harmala alkaloids have a high affinity on the active site of MPO (predicted free energies of binding up to −3.1 kcal/mol). Measurement of redox potentials versus the normal hydrogen electrode clearly differentiated (i) the high MPO inhibitory activity of harmine, harmaline and harmane (+1014, 1014 and 1003 mV, respectively); and (ii) the low activity of harmalol and harmol (+629/778 and 532/644 mV, respectively). A reverse phase HPLC method has been developed to determine simultaneously five alkaloids of Peganum harmala. Seeds contained all five β-carboline derivatives with the main active alkaloids, harmaline and harmine, being up to 3.8% and 2.9%, respectively. Up to 3.2% of harmine was determined in the roots. The four β-carboline derivatives, harmine, harmaline, harmane and harmalol were identified in the aerial parts. The highest inhibitory effect observed in seeds and the moderate effect of aerial parts could be explained by their harmine and harmaline content. In contrast, the very weak inhibition of the root extract, despite the presence of harmine, may tentatively be explained by the high concentration of harmol which can reduce Compound II of MPO to the native form.

Conclusion

The inhibition of MPO by Peganum harmala β-carboline alkaloids, herein reported for the first time, may explain the anti-inflammatory effect traditionally attributed to its herbal medicine.     

Accidental acetaminophen overdose

Acetaminophen is an OTC medication and amongst the most used pain relievers. It is the analgesic of first choice in pregnancy. Because of its low therapeutic index, accidental and suicidal acetaminophen intoxication is one of the most common causes of acute liver failure. Thus, face-to-face counselling of patients on the proper use of acetaminophen is essential for drug safety.