Transcriptomic Comparison of Human Peripartum and Dilated Cardiomyopathy Identifies Differences in Key Disease Pathways.

Peripartum cardiomyopathy (PPCM) is a rare form of acute onset heart failure that presents in otherwise healthy pregnant women around the time of delivery. While most of these women respond to early intervention, about 20% progress to end-stage heart failure that symptomatically resembles dilated cardiomyopathy (DCM). In this study, we examined two independent RNAseq datasets from the left ventricle of end-stage PPCM patients and compared gene expression profiles to female DCM and non-failing donors. Differential gene expression, enrichment analysis and cellular deconvolution were performed to identify key processes in disease pathology. PPCM and DCM display similar enrichment in metabolic pathways and extracellular matrix remodeling suggesting these are similar processes across end-stage systolic heart failure. Genes involved in golgi vesicles biogenesis and budding were enriched in PPCM left ventricles compared to healthy donors but were not found in DCM. Furthermore, changes in immune cell populations are evident in PPCM but to a lesser extent compared to DCM, where the latter is associated with pronounced pro-inflammatory and cytotoxic T cell activity. This study reveals several pathways that are common to end-stage heart failure but also identifies potential targets of disease that may be unique to PPCM and DCM.

Melatonin for rapid eye movement sleep behavior disorder in Parkinson's disease: A randomised controlled trial.

BACKGROUND: Melatonin may reduce REM-sleep behavior disorder (RBD) symptoms in Parkinson's disease (PD), though robust clinical trials are lacking. OBJECTIVE: To assess the efficacy of prolonged-release (PR) melatonin for RBD in PD. METHODS: Randomized, double-blind, placebo-controlled, parallel-group trial with an 8-week intervention and 4-week observation pre- and postintervention (ACTRN12613000648729). Thirty PD patients with rapid eye movement sleep behavior disorder were randomized to 4 mg of prolonged-release melatonin (Circadin) or matched placebo, ingested orally once-daily before bedtime. Primary outcome was the aggregate of rapid eye movement sleep behavior disorder incidents averaged over weeks 5 to 8 of treatment captured by a weekly diary. Data were included in a mixed-model analysis of variance (n = 15 per group). RESULTS: No differences between groups at the primary endpoint (3.4 events/week melatonin vs. 3.6 placebo; difference, 0.2; 95% confidence interval = -3.2 to 3.6; P = 0.92). Adverse events included mild headaches, fatigue, and morning sleepiness (n = 4 melatonin; n = 5 placebo). CONCLUSION: Prolonged-release melatonin 4 mg did not reduce rapid eye movement sleep behavior disorder in PD. © 2019 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

Clinical outcomes of locking stand-alone cage versus anterior plate construct in two-level anterior cervical discectomy and fusion: a systematic review and meta-analysis.

BACKGROUND: Two-level cervical degenerative disc disease (cDDD) can be effectively treated by anterior cervical discectomy and fusion (ACDF) similarly to single-level cDDD. Traditionally an anterior plate construct (APC) approach has been utilized, but ACDF without plate with a locking stand-alone cage (LSC) approach has emerged as an alternative option. The aim of this study was to compare the clinical outcome of LSC and APC in contiguous two-level ACDF used to treat cDDD the current literature. METHODS: Searches of seven electronic databases from inception to March 2018 were conducted following preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines. Extracted data were analysed using meta-analysis of proportions. RESULTS: The nine observational studies that satisfied all criteria described a pooled cohort of 687 contiguous two-level cDDD cases managed by ACDF, with 302 (44%) and 385 (56%) managed by LSC and APC approaches, respectively. When compared with APC, LSC was associated with significantly increased subsidence likelihood (OR 2.75; p < 0.001), greater disc height (MD 0.60 mm; p = 0.04) and reduced cervical lordosis (MD - 2.52°; p = 0.04) at last follow-up. Operative outcomes, fusion rates, functional scores and postoperative dysphagia rates were comparable. CONCLUSION: Although significant radiological differences were most evident, the comparability between LSC and APC in contiguous two-level ACDF with respect to all other clinical outcomes does not implicate one approach as clearly superior to the other in two-level ACDF. Larger, randomized studies with longer follow-up are required to delineate outcomes further to validate the findings of this study. These slides can be retrieved under Electronic Supplementary Material.

Anterior Lumbar Interbody Fusion in Left-sided Inferior Vena Cava and Right-sided Aortic Arch.

Spinal fusion via anterior lumbar interbody fusion (ALIF) can offer symptomatic relief to patients that suffer severe low back pain, radiculopathy, and claudication. However, a detailed working knowledge of the thoracic, abdominal, and lumbar anatomy, particularly of the vasculature, is vital. We report the case of a 68-year-old man who presented with radiculopathy and progressively worsening low back pain despite 9 months of unsuccessful conservative therapy and pain management. Preoperative computed tomography and magnetic resonance imaging revealed a rare anatomical variation, with an anomalous left-sided inferior vena cava and anomalous aorta. The patient was surgically treated with ALIF at L4,5 and L5 S1 via an altered surgical window. Given the anomalous anatomy of the patient, instead of performing the procedure after mobilizing both of the transposed abdominal great vessels, the inferior vena cava and the abdominal aorta, the ALIF was uneventfully performed in the window between these vessels. There were no perioperative or postoperative complications. At 12-week postoperative follow-up, X-ray imaging demonstrated successful implantation of ALIF cages with no recurrence of symptoms. A detailed working knowledge of anatomy is important, particularly if anatomical variations are present. This has implications for preoperative surgical planning, which is integral to the safety and the success of procedures.

Identification of acetyltransferase genes (HAT1 and KAT8) regulating HBV replication by RNAi screening.

BACKGROUND: The initiation of hepatitis B virus (HBV) replication involves the formation of covalently closed circular DNA (cccDNA) and its transcription into pregenomic RNA (pgRNA) in hepatocyte nuclei. The regulatory mechanism of HBV replication by acetyltransferase is thus far not well understood, but human acetyltransferase has been reported as being involved in the regulation of HBV replication. RESULTS: Depletion of KAT8 or HAT1 via RNA interference (RNAi) markedly down-regulated HBV-DNA and pgRNA levels in HepG2.2.15 cells, with KAT8 knockdown reducing both HBsAg and HBeAg more than HAT1 knockdown. Consistent with these observations, HBV replication regulators hepatocyte nuclear factor-4-α (HNF4α) and peroxisome proliferator-activated receptor gamma coactivator- (PPARGC-) 1-α were decreased following knockdown of HAT1 or KAT8. CONCLUSIONS: These data suggest that KAT8 or HAT1 regulate HBV replication and may be potential drug targets of anti-HBV therapy.

Molecular functions of the iron-regulated metastasis suppressor, NDRG1, and its potential as a molecular target for cancer therapy.

N-myc down-regulated gene 1 (NDRG1) is a known metastasis suppressor in multiple cancers, being also involved in embryogenesis and development, cell growth and differentiation, lipid biosynthesis and myelination, stress responses and immunity. In addition to its primary role as a metastasis suppressor, NDRG1 can also influence other stages of carcinogenesis, namely angiogenesis and primary tumour growth. NDRG1 is regulated by multiple effectors in normal and neoplastic cells, including N-myc, histone acetylation, hypoxia, cellular iron levels and intracellular calcium. Further, studies have found that NDRG1 is up-regulated in neoplastic cells after treatment with novel iron chelators, which are a promising therapy for effective cancer management. Although the pathways by which NDRG1 exerts its functions in cancers have been documented, the relationship between the molecular structure of this protein and its functions remains unclear. In fact, recent studies suggest that, in certain cancers, NDRG1 is post-translationally modified, possibly by the activity of endogenous trypsins, leading to a subsequent alteration in its metastasis suppressor activity. This review describes the role of this important metastasis suppressor and discusses interesting unresolved issues regarding this protein.