The study of antiphospholipid antibodies in recurrent pregnancy loss

Background: Around 15% of clinically recognised pregnancies in women less than 35 years old result in spontaneous miscarriage. However recurrent pregnancy loss (RPL) is encountered in 5% of couples with two or more losses and in around 1–2% of couples with three or more losses. In view of the increasing burden of recurrent pregnancy loss in the society and in view of Anti-phospholipid syndrome being one of the undisputed treatable cause for recurrent pregnancy loss, this study aims to evaluate the significance of the antibody profiles of APS in relation to RPL in OBG dept of VIMS and RC.Methods: Patients coming to the Obstetric and Gynaecology department of Vydehi Institute of Medical Sciences and Research Centre, Bangalore, from December 1st 2014 to June 30th 2016. A detailed history of patients was taken based on set questionnaires. Detailed general and gynaecological examination findings were taken. Routine blood investigations were sent along with investigations for aPLAs which included: - Lupus Anticoagulant (LA) - Anti Cardiolipin Antibody (ACA) - Anti β2 glycoprotein 1 (Anti-β2GP1Ab). Final results are statistically evaluated.Results: A total of 56 patients of recurrent miscarriage with two or more prior pregnancy losses were considered. Out of the 56 patients, 23 patients were excluded as per the exclusion criteria and 33 patients were included in the present study. The mean age of the study group was 24.63 years (Range: 20-32 years). Overall, seven patients (21.21%) were seen to have positive antiphospholipid antibody titers amongst the 33 patients, with repeat testing done after 12 weeks to confirm the positivity. Five patients (15.15%) were positive for ACA antibody. Four (12.12%) patients were positive for LA and B2GP1 each. Two patients (6.06%) were positive for both LA and ACA antibodies. Two patients (6.06%) were positive for LA and B2GP1 antibodies and two other (6.06%) patients were positive for ACA and Anti-β2GP1Ab. There was a statistically significant association noticed between ACA positivity and POG at 1st pregnancy loss. However, the overall association of APLA positivity and POG at pregnancy loss was not statistically significant.Conclusions: There was a significant difference of POG at first pregnancy loss in ACA positive patients as compared to the ACA negative patients. However, when all the APLA positive patients were considered the difference was not statistically significant

Persistent circulating platelet and endothelial derived microparticle signature may explain on-going pro-thrombogenicity after acute coronary syndrome

Aims: Microparticles (MPs) are submicron vesicles, released from activated, and apoptotic cells. MPs are elevated in the circulation of patients with coronary artery disease (CAD) and have pro-thrombotic potential. However, limited data exists on MP signature over time following an acute coronary event. / Methods & results: Circulating total annexin v + (Anv+) MPs of endothelial (EMP), platelet (PMP), monocyte (MMP), neutrophil (NMP) and smooth muscle cell (SMMP) origin were quantified by flow cytometry. 13 patients with acute coronary syndrome (ACS) were prospectively enrolled and 12 patients with stable angina (SA) were included as a comparator group. A panel of MP was measured at baseline, after percutaneous coronary intervention (PCI) and at days 1, 7, 30 and 6 months. Intra & inter group comparison was made between various time points. MP mediated thrombin generation was measured by recording lag phase, velocity index, peak thrombin and endogenous thrombin potential at these time points and compared with healthy controls. The total AnV+ MP levels were similar in ACS and SA groups at baseline, peaked immediately after PCI and were at their lowest on day 1. PMP & EMP levels remained significantly elevated in ACS patients at 6 months when compared to SA. No such difference was noted with NMP, MMP and SMMP. Patients with coronary artery disease showed abnormal thrombograms when compared to controls. Peak thrombin (nano moles) was significantly higher in CAD when compared to controls (254 IQR [226, 239] in ACS, 255 IQR [219, 328] in SA and 132 IQR [57, 252] in controls; p = 0.006). Differences in thrombin generation between ACS and SA were not significant (p = 1). Furthermore, thrombin parameters remained abnormal in ACS & SA patients at 6 months. / Conclusions: Total MP and individual MP phenotypes were significantly elevated after PCI reflecting endothelial injury. Elevated PMP and EMP levels at 6 months in ACS patients is suggestive of on-going inflammation, endothelial injury and may explain on-going pro-thrombogenicity seen up to 6 months after ACS despite dual antiplatelet therapy

Intracoronary platelet and monocyte activation status within platelet-monocyte complexes are determinants of inflammation in ST elevation myocardial infarction1

INTRODUCTION: Platelet Monocyte Complexes (PMCs) are commonly expressed in coronary artery disease but their pathologic significance in ST elevation myocardial infarction (STEMI) is unclear. This study evaluates the relationship between locally activated PMCs and intracoronary inflammation in stable and unstable coronary disease. MATERIAL AND METHODS: Micro catheter aspirated blood samples of 15 STEMI and 7 stable angina patients are collected from the coronary artery (CA), aorta (AO) and right atrium (RA). Samples are labelled with monoclonal antibodies and prepared for flow cytometry. CD 14 and CD 61 double positive cells are identified as PMC. P-selectin expression is identified by additional CD62P positivity and TF expression by additional CD142 positivity. Plasma TNF-alpha and IL-6 are measured using ELISA and CRP is measured in plasma using a high sensitivity automated microparticle enhanced latex turbidimetric immunoassay. RESULTS: No site-specific difference is seen in overall PMC expression in STEMI or stable angina. Surface P-selectin expression in STEMI [median (IQR)] is significantly higher in CA [35.01 (23.15-56.99)] compared with AO [15.99 (10.3-18.85)] or RA [14.02 (10.42-26.08)] (p = 0.003). Intracoronary PMC correlates significantly with intracoronary TNF-alpha (r = 0.87, p = 0.001) and intracoronary IL-6 (r = 0.76, p = 0.03). Bound monocytes within P-selectin positive and tissue factor positive complexes correlate positively with intracoronary TNF-alpha (r = 0.81, p = 0.008 & r = 0.80, p = 0.009 respectively) and IL-6 (r = 0.54, p = 0.16 & r = 0.71, p = 0.05 respectively). No such correlation is observed in the peripheral circulation of STEMI and stable angina patients. CONCLUSION: Inflammation is not attributable to PMC formation per se. However, increased intracoronary P-selectin expression by activated platelets and tissue factor expression by activated monocytes within the complexes are determinants of local intracoronary inflammatory burden in STEMI

Association of systemic inflammatory biomarkers with morphological characteristics of coronary atherosclerotic plaque by intravascular optical coherence tomography

Despite significant advances in preventive, medical, and interventional management, coronary artery disease remains the leading cause of death worldwide. We now know that in the majority of acute coronary syndromes, a thrombotic event is triggered either by the rupture or erosion of the so-called high-risk or ‘vulnerable’ plaque. However, accurately identifying the individual who is at significant risk of acute event remains the holy grail of preventive cardiology. To better stratify an individual's risk of developing and suffering a cardiovascular event, biomarkers are needed that can accurately predict coronary events and, if possible, monitor disease activity in response to medical or interventional therapies. In order to be able to understand the association of these biomarkers with the morphological substrate of high-risk plaques, intravascular imaging modalities can provide invaluable assistance. Novel imaging tools such as optical coherence tomography (OCT) have not only helped in identifying atherosclerotic plaque characteristics that are unstable but also in estimating global plaque burden. In this study, we provide an overview of our current knowledge of association of various inflammatory markers with atherosclerotic plaque characteristics seen on OCT

Microparticles and their role in coronary artery disease.

Despite significant advances in prevention, medical and interventional management, coronary artery disease (CAD) remains the leading cause of death worldwide. Although the number of people being diagnosed with CAD has plateaued in the western world, it is projected to increase significantly in the developing world reaching epidemic proportions, particularly in South Asia. To better stratify the risk of developing and suffering a cardiovascular event due to CAD, not only plasma biomarkers relating to disease burden but also disease activity in CAD are needed; this will allow targeting of appropriate management to high-risk patients for acute events. Over the last twenty years, data have emerged showing the role of sub-micron vesicles called microparticles (MPs) in the pathogenesis of formation and evolution of atherosclerotic plaques causing either stable angina (SA) or acute coronary syndromes (ACS). Herein we provide an overview of our current knowledge of MP formation, composition and possible mechanisms through which they could be contributing to CAD. We also reviewed currently available methods and their limitations in quantifying MPs and in determining their functional aspects. Role of various treatments ranging from dietary substitutes to oral medicines and intravenous medications to mechanistic procedures such as hemofiltration are elaborated. Although evidence implicating the role of MPs in CAD are mounting large scale prospective studies are still lacking and are the need of the hour prior to establishing the use of MPs as biomarkers for the early detection of CAD and its progression

Reduced Cardiovascular Reserve in Chronic Kidney Failure: A Matched Cohort Study

Background: Patients with chronic kidney failure (CKF) experience impaired functional cardiovascular reserve with reduced oxygen consumption at peak exercise (Vo2peak). No studies have examined whether this is related to impaired cardiovascular compliance as a consequence of loss of adaptive structural alterations, resulting from chronic uremia or hypertension. Study Design: Prospective matched-cohort study. Setting & Participants: We assessed CKF in parallel with patients with essential hypertension but without cardiovascular disease. Patients with CKF were either scheduled for kidney transplantation or transplant waitlisted. 80 patients with CKF and 80 with essential hypertension matched in age, sex, and body mass index were evaluated. 61 patients with CKF (76.3%) were dialysis dependent. Predictor: CKF versus essential hypertension without cardiovascular disease. Measurements & Outcomes: Vo2peak was measured during maximal exercise testing. 2-dimensional echocardiography and arterial applanation tonometry were performed prior to exercise testing. To evaluate for the difference in Vo2peak between study groups, statistically significant predictors of Vo2peak in multiple regression models were additionally assessed by fitting models comprising the interaction term of patient group with the predictor variable of interest. Results: Vo2peak was significantly lower in patients with CKF than those with essential hypertension (18.8 vs 24.5 mL/min·kg; P < 0.001). Independent predictors of Vo2peak for CKF included left ventricular (LV) filling pressure (E/mean e′; unstandardized regression coefficient: change in Vo2peak [in mL/min·kg] per 1-unit change of variable = −5.1) and pulse wave velocity (−4.0); in essential hypertension, these were LV mass index (0.2), LV end-diastolic volume index (0.4), peak heart rate (0.2), and pulse wave velocity (−8.8). The interaction effect of Vo2peak between patient groups with LV mass index (P < 0.001), LV end-diastolic volume index (P < 0.001), and peak heart rate (P < 0.01) were significantly stronger in the hypertension group, whereby higher values led to greater Vo2peak. Limitations: Skeletal muscle strength was not assessed. Conclusion: This study suggests that maladaptive LV changes, as well as blunted chronotropic response, are important mechanistic factors resulting in reduced cardiovascular reserve in patients with CKF, beyond predominantly vascular changes associated with hypertension

Microparticles in acute coronary syndrome

BACKGROUND: Emerging evidence supports the role of cell-derived microparticles (MPs) in the pathophysiology of acute coronary syndrome (ACS). OBJECTIVES: To explore the relationship between coronary and systemic MP levels, investigate the correlation between MPs, inflammatory markers and Troponin T in patients with ACS. METHODS: Thirty seven patients with ACS scheduled for percutaneous coronary interventions (PCI) were studied. Eleven patients with stable angina (SA) were included as a control group. AnnexinV+MPs (AnV+MPs) and activated platelet-monocyte aggregates (PMA) from right atrium (RA) and culprit coronary artery (CO) distal to culprit lesion were measured using flow cytometry. High sensitivity C-reactive protein (CRP), Interleukin - 6 (IL-6), tumour necrosis factor - α (TNF-α), serum amyloid A (SAA) and Troponin T were assayed. RESULTS: Total and cell specific AnV+MP expression were higher in the ACS group in both the CO and RA, with greater levels detected in the CO. Platelet activation showed positive correlation with Troponin-T and platelet MP in both CO and RA of the ACS group (r=0.4 for both; p=0.04 & p=0.03 respectively). Inflammatory markers levels did not differ between the ACS and SA patients. CONCLUSIONS: Elevated coronary and systemic MP levels and positive correlation of platelet activation with Troponin-T and platelet MPs suggest a pathogenic role for MPs in ACS

Yeast diversity in relation to the production of fuels and chemicals

In addition to ethanol, yeasts have the potential to produce many other industrially-relevant chemicals from numerous different carbon sources. However there remains a paucity of information about overall capability across the yeast family tree. Here, 11 diverse species of yeasts with genetic backgrounds representative of different branches of the family tree were investigated. They were compared for their abilities to grow on a range of sugar carbon sources, to produce potential platform chemicals from such substrates and to ferment hydrothermally pretreated rice straw under simultaneous saccharification and fermentation conditions. The yeasts differed considerably in their metabolic capabilities and production of ethanol. A number could produce significant amounts of ethyl acetate, arabinitol, glycerol and acetate in addition to ethanol, including from hitherto unreported carbon sources. They also demonstrated widely differing efficiencies in the fermentation of sugars derived from pre-treated rice straw biomass and differential sensitivities to fermentation inhibitors. A new catabolic property of Rhodotorula mucilaginosa (NCYC 65) was discovered in which sugar substrate is cleaved but the products are not metabolised. We propose that engineering this and some of the other properties discovered in this study and transferring such properties to conventional industrial yeast strains could greatly expand their biotechnological utility

Human cytomegalovirus immediate-early 1 protein rewires upstream STAT3 to downstream STAT1 signaling switching an IL6-type to an IFNγ-like response

MN and CP were supported by the Wellcome Trust (www.wellcome.ac.uk) Institutional Strategic Support Fund and CP was supported by the Deutsche Forschungsgemeinschaft (PA 815/2-1; www.dfg.de).The human cytomegalovirus (hCMV) major immediate-early 1 protein (IE1) is best known for activating transcription to facilitate viral replication. Here we present transcriptome data indicating that IE1 is as significant a repressor as it is an activator of host gene expression. Human cells induced to express IE1 exhibit global repression of IL6- and oncostatin M-responsive STAT3 target genes. This repression is followed by STAT1 phosphorylation and activation of STAT1 target genes normally induced by IFNγ. The observed repression and subsequent activation are both mediated through the same region (amino acids 410 to 445) in the C-terminal domain of IE1, and this region serves as a binding site for STAT3. Depletion of STAT3 phenocopies the STAT1-dependent IFNγ-like response to IE1. In contrast, depletion of the IL6 receptor (IL6ST) or the STAT kinase JAK1 prevents this response. Accordingly, treatment with IL6 leads to prolonged STAT1 instead of STAT3 activation in wild-type IE1 expressing cells, but not in cells expressing a mutant protein (IE1dl410-420) deficient for STAT3 binding. A very similar STAT1-directed response to IL6 is also present in cells infected with a wild-type or revertant hCMV, but not an IE1dl410-420 mutant virus, and this response results in restricted viral replication. We conclude that IE1 is sufficient and necessary to rewire upstream IL6-type to downstream IFNγ-like signaling, two pathways linked to opposing actions, resulting in repressed STAT3- and activated STAT1-responsive genes. These findings relate transcriptional repressor and activator functions of IE1 and suggest unexpected outcomes relevant to viral pathogenesis in response to cytokines or growth factors that signal through the IL6ST-JAK1-STAT3 axis in hCMV-infected cells. Our results also reveal that IE1, a protein considered to be a key activator of the hCMV productive cycle, has an unanticipated role in tempering viral replication.Publisher PDFPeer reviewe