Clinical features and management of erythromelalgia: long term follow-up of 46 cases

OBJECTIVES: To review our clinical experience of this rare condition and describe the clinical features and response to therapy in a cohort of patients with erythromelalgia (EM), a rare condition, characterised by paroxysmal hyperthermia of the extremities with erythema, pain and intense burning. METHODS: A review was made of the electronic and paper medical records of patients with the diagnosis of EM, with a telephone interview to verify and complete clinical information relating treatment and outcome. RESULTS: 46 patients (41 females) were included in this study. Mean age was 57 years and mean duration of symptoms was 16 years. Raynaud's phenomenon was present in 36 patients (80%) and 4 patients (9%) had systemic sclerosis. Smoking (current or previous) was identified as a possible risk factor in 26 cases and exposure to chronic vibration in 3 cases. Overall, the effect on quality of life was mild in 15% of cases, moderate in 30% and severe in 48%. The most common symptoms were burning (96%), heat (93%), pain (87%), and redness (83%). Symptoms affected the lower limbs in 98% of cases, upper limbs in 76%, face in 20% and trunk in 11%. Triggers included heat (85%), exercise (78%) and time of day (76%). Various medications were tried, showing poor effect in most cases. Intravenous iloprost was given to 27 patients, with benefit in 17 patients (63%). CONCLUSIONS: Erythromelalgia is a rare chronic debilitating condition. Exercise, heat and night time are common triggers. Current medical therapies are seldom effective and further research is sorely needed

Two-dimensional knowledge-based volumetric reconstruction of the right ventricle documents short-term improvement in pulmonary hypertension

BACKGROUND: Data are scarce about short-term right ventricular changes in pulmonary hypertension. Two-dimensional knowledge-based reconstruction of the right ventricle with 2D echocardiography (2DKBR) has been shown to be a valid alternative to Cardiac MRI. PATIENTS AND METHODS: In this longitudinal study 25 pulmonary hypertension patients underwent 2DKBR of the right ventricle, assessment of NT-proBNP levels and functional class at baseline and after a mean follow-up of 6.1 months. Patients were followed up clinically for a further mean of 8.2 months. The majority of patients had connective tissue disease (CTD) associated pulmonary arterial hypertension (n=15) or chronic thromboembolic pulmonary hypertension (CTEPH; n=6). A total of 15 patients underwent an intervention, either new targeted therapy, escalation of targeted therapy or pulmonary endarterectomy. A total of 10 clinically stable patients were routinely followed up without any change in therapy. RESULTS: There were significant improvements in the right ventricular end-diastolic volume index (111±29 mL/m² vs 100±36 mL/m²; P=.038), end-systolic volume index (72±23 mL/m² vs 61±25 mL/m²; P=.001), and ejection fraction (35±10% vs 40±9%; P=.030). Changes in NT-proBNP levels correlated strongest with changes in end-systolic volume index (r=-.77; P=<.0001). Four patients experienced clinical worsening during extended follow-up, dilatation of the right ventricle was associated with clinical worsening. CONCLUSION: In a CTD and CTEPH dominated patient population significant reverse remodeling and improvement of ejection fraction occurred despite a short follow-up and was paralleled by significant changes in NT-proBNP levels. Further right ventricular dilatation was associated with worse clinical outcome. 2DKBR is a feasible substitute for Cardiac MRI to follow-up right ventricular indices in pulmonary hypertension

Neprilysin inhibition for pulmonary arterial hypertension: a randomized, double-blind, placebo-controlled, proof-of-concept trial

This is the peer reviewed version of the following article: Hobbs AJ, Moyes AJ, Baliga RS, et al. Neprilysin inhibition for pulmonary arterial hypertension: a randomized, double‐blind, placebo‐controlled, proof‐of‐concept trial. Br J Pharmacol. 2019. https://doi.org/10.1111/bph.14621, which has been published in final form at https://doi.org/10.1111/bph.14621. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived VersionsThis work was supported by a British Heart Foundation Project Grant (PG/11/88/28992) and the National Institutes for Health Research, Comprehensive Biomedical Research Centre award to UC

Characteristics and Survival of Anti-U1 RNP Antibody-Positive Patients With Connective Tissue Disease-Associated Pulmonary Arterial Hypertension

OBJECTIVE: Pulmonary arterial hypertension (PAH) is a severe complication of connective tissue diseases (CTDs). This study aimed to investigate the clinical and hemodynamic characteristics and survival of anti-U1 RNP-positive patients with CTD-associated PAH, with a focus on systemic sclerosis (SSc)-associated PAH. METHODS: We implemented a prospective database that included patients with CTD-associated PAH for whom there were clinical, autoantibody, and mortality data. We compared clinical and hemodynamic characteristics to anti-U1 RNP antibody status. We then assessed whether anti-U1 RNP antibodies could be a prognostic factor in CTD-associated PAH with a focus on SSc-associated PAH. RESULTS: We studied a total of 342 patients with CTD-associated PAH, of whom 36 (11%) were anti-U1 RNP antibody positive. Anti-U1 RNP-positive patients were younger and less functionally impaired than were anti-U1 RNP-negative patients in CTD- and SSc-associated PAH. Hemodynamic parameters were similar in anti-U1 RNP-positive and anti-U1 RNP-negative patients. In CTD-associated PAH, anti-U1 RNP positivity was associated with decreased mortality in univariable analysis (hazard ratio 0.34 [95% confidence interval 0.18-0.65], P < 0.001). In multivariable analysis, anti-U1 RNP positivity was also associated with decreased mortality (hazard ratio 0.44 [95% confidence interval 0.20-0.97], P = 0.043) independently of age, sex, functional parameters, lung involvement, and hemodynamic parameters. Results were similar in SSc-associated PAH, although the association between anti-U1 RNP positivity and survival did not reach significance in univariable (hazard ratio 0.47 [95% confidence interval 0.22-1.02], P = 0.055) and multivariable (hazard ratio 0.47 [95% confidence interval 0.20-1.11], P = 0.085) analyses. CONCLUSION: Anti-U1 RNP positivity was associated with distinct clinical characteristics and survival in CTD- and SSc-associated PAH. While hemodynamic parameters were similar in anti-U1 RNP-positive and anti-U1 RNP-negative patients, our results suggest that anti-U1 RNP positivity could be a factor protecting against mortality in CTD- and SSc-associated PAH

Optical coherence tomography evaluation of pulmonary arterial vasculopathy in Systemic Sclerosis

Our current understanding of the pathophysiology of pulmonary vascular disease is incomplete, since information about alterations of the pulmonary vasculature in pulmonary arterial hypertension (PAH) is primarily provided by autopsy or tissue specimens. The aim of this study was to compare the distal pulmonary vasculature of <2 mm in diameter in Systemic Sclerosis (SSc) patients with (n = 17) and without (n = 5) associated PAH using Optical Coherence Tomography during Right Heart catheterization. SSc-PAH patients showed significant thickening of Intima Media Thickening Area compared to patients without PAH (27 +/- 5.8% vs. 21 +/- 1.4%, p = 0.024). A good haemodynamic response to previous targeted PAH treatment was associated with a significantly greater number of small pulmonary artery side branches <300 μm per cm vessel (3.8 +/- 1.1 vs. 1.8 +/- 1.1; p = 0.010) and not associated with Intima Media thickening Area (26 +/- 5.4% vs. 28 +/- 6.7%; p = 0.6). Unexpected evidence of pulmonary artery thrombus formation was found in 19% of SSc-PAH patients. This is the first in-vivo study demonstrating a direct link between a structural abnormality of pulmonary arteries and a response to targeted treatment in PAH. Intravascular imaging may identify subgroups that may benefit from anticoagulation

Mapping Dynamic Histone Acetylation Patterns to Gene Expression in Nanog-depleted Murine Embryonic Stem Cells

Embryonic stem cells (ESC) have the potential to self-renew indefinitely and to differentiate into any of the three germ layers. The molecular mechanisms for self-renewal, maintenance of pluripotency and lineage specification are poorly understood, but recent results point to a key role for epigenetic mechanisms. In this study, we focus on quantifying the impact of histone 3 acetylation (H3K9,14ac) on gene expression in murine embryonic stem cells. We analyze genome-wide histone acetylation patterns and gene expression profiles measured over the first five days of cell differentiation triggered by silencing Nanog, a key transcription factor in ESC regulation. We explore the temporal and spatial dynamics of histone acetylation data and its correlation with gene expression using supervised and unsupervised statistical models. On a genome-wide scale, changes in acetylation are significantly correlated to changes in mRNA expression and, surprisingly, this coherence increases over time. We quantify the predictive power of histone acetylation for gene expression changes in a balanced cross-validation procedure. In an in-depth study we focus on genes central to the regulatory network of Mouse ESC, including those identified in a recent genome-wide RNAi screen and in the PluriNet, a computationally derived stem cell signature. We find that compared to the rest of the genome, ESC-specific genes show significantly more acetylation signal and a much stronger decrease in acetylation over time, which is often not reflected in an concordant expression change. These results shed light on the complexity of the relationship between histone acetylation and gene expression and are a step forward to dissect the multilayer regulatory mechanisms that determine stem cell fate.Comment: accepted at PLoS Computational Biolog

Monophasic synovial sarcoma of the pharynx: a case report

Synovial sarcomas are a rare form of soft tissue sarcomas. We present a case of a 62 year-old male presenting with a left thyroid lump initially though to be a thyroid adenoma but subsequently diagnosed as a monophasic synovial sarcoma of the pharynx. We discuss the diagnosis and treatment of this case

The identification of genes important in pseudomonas syringae pv. phaseolicola plant colonisation using in vitro screening of transposon libraries

The bacterial plant pathogen Pseudomonas syringae pv. phaseolicola (Pph) colonises the surface of common bean plants before moving into the interior of plant tissue, via wounds and stomata. In the intercellular spaces the pathogen proliferates in the apoplastic fluid and forms microcolonies (biofilms) around plant cells. If the pathogen can suppress the plant’s natural resistance response, it will cause halo blight disease. The process of resistance suppression is fairly well understood, but the mechanisms used by the pathogen in colonisation are less clear. We hypothesised that we could apply in vitro genetic screens to look for changes in motility, colony formation, and adhesion, which are proxies for infection, microcolony formation and cell adhesion. We made transposon (Tn) mutant libraries of Pph strains 1448A and 1302A and found 106/1920 mutants exhibited alterations in colony morphology, motility and biofilm formation. Identification of the insertion point of the Tn identified within the genome highlighted, as expected, a number of altered motility mutants bearing mutations in genes encoding various parts of the flagellum. Genes involved in nutrient biosynthesis, membrane associated proteins, and a number of conserved hypothetical protein (CHP) genes were also identified. A mutation of one CHP gene caused a positive increase in in planta bacterial growth. This rapid and inexpensive screening method allows the discovery of genes important for in vitro traits that can be correlated to roles in the plant interactio

Long-term follow-up with Granulocyte and Monocyte Apheresis re-treatment in patients with chronically active inflammatory bowel disease

<p>Abstract</p> <p>Background</p> <p>Patients with IBD and chronic inflammation refractory to conventional therapy often demonstrate higher risk of serious complications. Combinations of immunosuppression and biological treatment as well as surgical intervention are often used in this patient group. Hence, there is need for additional treatment options. In this observational study, focused on re-treatment and long-term results, Granulocyte/Monocyte Adsorption (GMA, Adacolumn^®) treatment has been investigated to study efficacy, safety and quality of life in IBD-patients with chronic activity.</p> <p>Methods</p> <p>Fifteen patients with ulcerative colitis and 25 patients with Crohn's disease, both groups with chronically active inflammation refractory to conventional medication were included in this observational study. The patients received 5-10 GMA sessions, and the clinical activity was assessed at baseline, after each completed course, and at week 10 and 20 by disease activity index, endoscopy and quality of life evaluation. Relapsed patients were re-treated by GMA in this follow-up study up to 58 months.</p> <p>Results</p> <p>Clinical response was seen in 85% and complete remission in 65% of the patients. Ten patients in the UC-group (66%) and 16 patients in the CD-group (64%) maintained clinical and endoscopic remission for an average of 14 months. Fourteen patients who relapsed after showing initial remission were re-treated with GMA and 13 (93%) went into a second remission. Following further relapses, all of seven patients were successfully re-treated for the third time, all of three patients for the fourth time and one for a fifth time.</p> <p>Conclusions</p> <p>IBD-patients with chronic inflammation despite conventional therapy seem to benefit from GMA. Re-treatment of relapsing remission patients seems to be effective.</p

Discovery and characterization of chromatin states for systematic annotation of the human genome

A plethora of epigenetic modifications have been described in the human genome and shown to play diverse roles in gene regulation, cellular differentiation and the onset of disease. Although individual modifications have been linked to the activity levels of various genetic functional elements, their combinatorial patterns are still unresolved and their potential for systematic de novo genome annotation remains untapped. Here, we use a multivariate Hidden Markov Model to reveal 'chromatin states' in human T cells, based on recurrent and spatially coherent combinations of chromatin marks. We define 51 distinct chromatin states, including promoter-associated, transcription-associated, active intergenic, large-scale repressed and repeat-associated states. Each chromatin state shows specific enrichments in functional annotations, sequence motifs and specific experimentally observed characteristics, suggesting distinct biological roles. This approach provides a complementary functional annotation of the human genome that reveals the genome-wide locations of diverse classes of epigenetic function.National Science Foundation (U.S.). (Award 0905968)National Human Genome Research Institute (U.S.) (Award U54-HG004570)National Human Genome Research Institute (U.S.) (Award RC1-HG005334