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

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

Analyzing models of work addiction: single factor and bi-factor models of the Bergen Work Addiction Scale

Work addiction ('workaholism') has become an increasingly studied topic in the behavioral addictions literature and had led to the development of a number of instruments to assess it. One such instrument is the Bergen Work Addiction Scale (BWAS - Andreassen et al. 2012 Scandinavian Journal of Psychology, 53, 265-272). However, the BWAS has never been investigated in Eastern-European countries. The goal of the present study was to examine the factor structure, the reliability and cut-off scores of the BWAS in a comprehensive Hungarian sample. This study is a direct extension of the original validation of BWAS by providing results on the basis of representative data and the development of appropriate cut-off scores The study utilized an online questionnaire with a Hungarian representative sample including 500 respondents (F = 251; M age = 35.05 years) who completed the BWAS. A series of confirmatory factor analyses were carried out leading to a short, 7-item first-order factor structure and a longer 14-item seven-factor nested structure. Despite the good validity of the longer version, its reliability was not as high as it could have been. One-fifth (20.6 %) of the Hungarians who used the internet at least weekly were categorized as work addicts using the BWAS. It is recommended that researchers use the original seven items from the Norwegian scale in order to facilitate and stimulate cross-national research on addiction to work

Characterization of early host responses in adults with dengue disease

BACKGROUND: While dengue-elicited early and transient host responses preceding defervescence could shape the disease outcome and reveal mechanisms of the disease pathogenesis, assessment of these responses are difficult as patients rarely seek healthcare during the first days of benign fever and thus data are lacking. METHODS: In this study, focusing on early recruitment, we performed whole-blood transcriptional profiling on dengue virus PCR positive patients sampled within 72 h of self-reported fever presentation (average 43 h, SD 18.6 h) and compared the signatures with autologous samples drawn at defervescence and convalescence and to control patients with fever of other etiology. RESULTS: In the early dengue fever phase, a strong activation of the innate immune response related genes were seen that was absent at defervescence (4-7 days after fever debut), while at this second sampling genes related to biosynthesis and metabolism dominated. Transcripts relating to the adaptive immune response were over-expressed in the second sampling point with sustained activation at the third sampling. On an individual gene level, significant enrichment of transcripts early in dengue disease were chemokines CCL2 (MCP-1), CCL8 (MCP-2), CXCL10 (IP-10) and CCL3 (MIP-1α), antimicrobial peptide β-defensin 1 (DEFB1), desmosome/intermediate junction component plakoglobin (JUP) and a microRNA which may negatively regulate pro-inflammatory cytokines in dengue infected peripheral blood cells, mIR-147 (NMES1). CONCLUSIONS: These data show that the early response in patients mimics those previously described in vitro, where early assessment of transcriptional responses has been easily obtained. Several of the early transcripts identified may be affected by or mediate the pathogenesis and deserve further assessment at this timepoint in correlation to severe disease

TISs-ST: a web server to evaluate polymorphic translation initiation sites and their reflections on the secretory targets

<p>Abstract</p> <p>Background</p> <p>The nucleotide sequence flanking the translation initiation codon (start codon context) affects the translational efficiency of eukaryotic mRNAs, and may indicate the presence of an alternative translation initiation site (TIS) to produce proteins with different properties. Multi-targeting may reflect the translational variability of these other protein forms. In this paper we present a web server that performs computations to investigate the usage of alternative translation initiation sites for the synthesis of new protein variants that might have different functions.</p> <p>Results</p> <p>An efficient web-based tool entitled TISs-ST (Translation Initiation Sites and Secretory Targets) evaluates putative translation initiation sites and indicates the prediction of a signal peptide of the protein encoded from this site. The TISs-ST web server is freely available to both academic and commercial users and can be accessed at <url>http://ipe.cbmeg.unicamp.br/pub/TISs-ST</url>.</p> <p>Conclusion</p> <p>The program can be used to evaluate alternative translation initiation site consensus with user-specified sequences, based on their composition or on many position weight matrix models. TISs-ST provides analytical and visualization tools for evaluating the periodic frequency, the consensus pattern and the total information content of a sequence data set. A search option allows for the identification of signal peptides from predicted proteins using the PrediSi software.</p

Local and Global Effects of Climate on Dengue Transmission in Puerto Rico

The four dengue viruses, the agents of dengue fever and dengue hemorrhagic fever in humans, are transmitted predominantly by the mosquito Aedes aegypti. The abundance and the transmission potential of Ae. aegypti are influenced by temperature and precipitation. While there is strong biological evidence for these effects, empirical studies of the relationship between climate and dengue incidence in human populations are potentially confounded by seasonal covariation and spatial heterogeneity. Using 20 years of data and a statistical approach to control for seasonality, we show a positive and statistically significant association between monthly changes in temperature and precipitation and monthly changes in dengue transmission in Puerto Rico. We also found that the strength of this association varies spatially, that this variation is associated with differences in local climate, and that this relationship is consistent with laboratory studies of the impacts of these factors on vector survival and viral replication. These results suggest the importance of temperature and precipitation in the transmission of dengue viruses and suggest a reason for their spatial heterogeneity. Thus, while dengue transmission may have a general system, its manifestation on a local scale may differ from global expectations

Statistical Metamodeling for Revealing Synergistic Antimicrobial Interactions

Many bacterial pathogens are becoming drug resistant faster than we can develop new antimicrobials. To address this threat in public health, a metamodel antimicrobial cocktail optimization (MACO) scheme is demonstrated for rapid screening of potent antibiotic cocktails using uropathogenic clinical isolates as model systems. With the MACO scheme, only 18 parallel trials were required to determine a potent antimicrobial cocktail out of hundreds of possible combinations. In particular, trimethoprim and gentamicin were identified to work synergistically for inhibiting the bacterial growth. Sensitivity analysis indicated gentamicin functions as a synergist for trimethoprim, and reduces its minimum inhibitory concentration for 40-fold. Validation study also confirmed that the trimethoprim-gentamicin synergistic cocktail effectively inhibited the growths of multiple strains of uropathogenic clinical isolates. With its effectiveness and simplicity, the MACO scheme possesses the potential to serve as a generic platform for identifying synergistic antimicrobial cocktails toward management of bacterial infection in the future

Bezielle Selectively Targets Mitochondria of Cancer Cells to Inhibit Glycolysis and OXPHOS

Bezielle (BZL101) is a candidate oral drug that has shown promising efficacy and excellent safety in the early phase clinical trials for advanced breast cancer. Bezielle is an aqueous extract from the herb Scutellaria barbata. We have reported previously that Bezielle was selectively cytotoxic to cancer cells while sparing non-transformed cells. In tumor, but not in non-transformed cells, Bezielle induced generation of ROS and severe DNA damage followed by hyperactivation of PARP, depletion of the cellular ATP and NAD, and inhibition of glycolysis. We show here that tumor cells' mitochondria are the primary source of reactive oxygen species induced by Bezielle. Treatment with Bezielle induces progressively higher levels of mitochondrial superoxide as well as peroxide-type ROS. Inhibition of mitochondrial respiration prevents generation of both types of ROS and protects cells from Bezielle-induced death. In addition to glycolysis, Bezielle inhibits oxidative phosphorylation in tumor cells and depletes mitochondrial reserve capacity depriving cells of the ability to produce ATP. Tumor cells lacking functional mitochondria maintain glycolytic activity in presence of Bezielle thus supporting the hypothesis that mitochondria are the primary target of Bezielle. The metabolic effects of Bezielle towards normal cells are not significant, in agreement with the low levels of oxidative damage that Bezielle inflicts on them. Bezielle is therefore a drug that selectively targets cancer cell mitochondria, and is distinguished from other such drugs by its ability to induce not only inhibition of OXPHOS but also of glycolysis. This study provides a better understanding of the mechanism of Bezielle's cytotoxicity, and the basis of its selectivity towards cancer cells