The use of novel oral anticoagulants compared to vitamin K antagonists (warfarin) in patients with left ventricular thrombus after acute myocardial infarction.

AIM: Current guidelines recommend the use of vitamin K antagonist (VKA) for up to 3-6 months for treatment of left ventricular (LV) thrombus post-acute myocardial infarction (AMI). However, based on evidence supporting non-inferiority of novel oral anticoagulants (NOAC) compared to VKA for other indications such as deep vein thrombosis, pulmonary embolism (PE), and thromboembolic prevention in atrial fibrillation, NOACs are being increasingly used off licence for the treatment of LV thrombus post-AMI. In this study, we investigated the safety and effect of NOACs compared to VKA on LV thrombus resolution in patients presenting with AMI. METHODS AND RESULTS: This was an observational study of 2328 consecutive patients undergoing coronary angiography ± percutaneous coronary intervention (PCI) for AMI between May 2015 and December 2018, at a UK cardiac centre. Patients' details were collected from the hospital electronic database. The primary endpoint was rate of LV thrombus resolution with bleeding rates a secondary outcome. Left ventricular thrombus was diagnosed in 101 (4.3%) patients. Sixty patients (59.4%) were started on VKA and 41 patients (40.6%) on NOAC therapy (rivaroxaban: 58.5%, apixaban: 36.5%, and edoxaban: 5.0%). Both groups were well matched in terms of baseline characteristics including age, previous cardiac history (previous myocardial infarction, PCI, coronary artery bypass grafting), and cardiovascular risk factors (hypertension, diabetes, hypercholesterolaemia). Over the follow-up period (median 2.2 years), overall rates of LV thrombus resolution were 86.1%. There was greater and earlier LV thrombus resolution in the NOAC group compared to patients treated with warfarin (82% vs. 64.4%, P = 0.0018, at 1 year), which persisted after adjusting for baseline variables (odds ratio 1.8, 95% confidence interval 1.2-2.9). Major bleeding events during the follow-up period were lower in the NOAC group, compared with VKA group (0% vs. 6.7%, P = 0.030) with no difference in rates of systemic thromboembolism (5% vs. 2.4%, P = 0.388). CONCLUSION: These data suggest improved thrombus resolution in post-acute coronary syndrome (ACS) LV thrombosis in patients treated with NOACs compared to VKAs. This improvement in thrombus resolution was accompanied with a better safety profile for NOAC patients vs. VKA-treated patients. Thus, provides data to support a randomized trial to answer this question.

Does the presence of conflict affect maternal and neonatal mortality during Caesarean sections?

INTRODUCTION: Conflicts frequently occur in countries with high maternal and neonatal mortality and can aggravate difficulties accessing emergency care. No literature is available on whether the presence of conflict influences the outcomes of mothers and neonates during Caesarean sections (C-sections) in high-mortality settings. OBJECTIVE: To determine whether the presence of conflict was associated with changes in maternal and neonatal mortality during C-sections. METHODS: We analysed routinely collected data on C-sections from 17 Médecins Sans Frontières (MSF) health facilities in 12 countries. Exposure variables included presence and intensity of conflict, type of health facility and other types of access to emergency care. RESULTS: During 2008-2015, 30,921 C-sections were performed in MSF facilities; of which 55.4% were in areas of conflict. No differences were observed in maternal mortality in conflict settings (0.1%) vs. non-conflict settings (0.1%) (P = 0.08), nor in neonatal mortality between conflict (12.2%) and non-conflict settings (11.5%) (P = 0.1). Among the C-sections carried out in conflict settings, neonatal mortality was slightly higher in war zones compared to areas of minor conflict (P = 0.02); there was no difference in maternal mortality (P = 0.38). CONCLUSIONS: Maternal and neonatal mortality did not appear to be affected by the presence of conflict in a large number of MSF facilities. This finding should encourage humanitarian organisations to support C-sections in conflict settings to ensure access to quality maternity care.

Respiratory health status is associated with treatment outcomes in pulmonary tuberculosis.

The association between respiratory impairment and tuberculosis (TB) treatment outcomes is not clear. We prospectively evaluated respiratory health status, measured using the Saint George's Respiratory Questionnaire (SGRQ), in a cohort of new adult pulmonary TB cases during and up to 18 months following treatment in India. Associations between total SGRQ scores and poor treatment outcomes of failure, recurrence and all-cause death were measured using multivariable Poisson regression. We enrolled 455 participants contributing 619 person-years at risk; 39 failed treatment, 23 had recurrence and 16 died. The median age was 38 years (interquartile range 26-49); 147 (32%) ever smoked. SGRQ scores at treatment initiation were predictive of death during treatment (14% higher risk per 4-point increase in baseline SGRQ scores, 95%CI 2-28, P = 0.01). Improvement in SGRQ scores during treatment was associated with a lower risk of failure (1% lower risk for every per cent improvement during treatment, 95%CI 1-2, P = 0.05). Clinically relevant worsening in SGRQ scores following successful treatment was associated with a higher risk of recurrence (15% higher risk per 4-point increase scores, 95%CI 4-27, P = 0.004). Impaired respiratory health status was associated with poor TB treatment outcomes. The SGRQ may be used to monitor treatment response and predict the risk of death in pulmonary TB. .

Surfaceome profiling enables isolation of cancer-specific exosomal cargo in liquid biopsies from pancreatic cancer patients.

Background: Detection of circulating tumor DNA can be limited due to their relative scarcity in circulation, particularly while patients are actively undergoing therapy. Exosomes provide a vehicle through which cancer-specific material can be enriched from the compendium of circulating non-neoplastic tissue-derived nucleic acids. We carried out a comprehensive profiling of the pancreatic ductal adenocarcinoma (PDAC) exosomal 'surfaceome' in order to identify surface proteins that will render liquid biopsies amenable to cancer-derived exosome enrichment for downstream molecular profiling. Patients and methods: Surface exosomal proteins were profiled in 13 human PDAC and 2 non-neoplastic cell lines by liquid chromatography-mass spectrometry. A total of 173 prospectively collected blood samples from 103 PDAC patients underwent exosome isolation. Droplet digital PCR was used on 74 patients (136 total exosome samples) to determine baseline KRAS mutation call rates while patients were on therapy. PDAC-specific exosome capture was then carried out on additional 29 patients (37 samples) using an antibody cocktail directed against selected proteins, followed by droplet digital PCR analysis. Exosomal DNA in a PDAC patient resistant to therapy were profiled using a molecular barcoded, targeted sequencing panel to determine the utility of enriched nucleic acid material for comprehensive molecular analysis. Results: Proteomic analysis of the exosome 'surfaceome' revealed multiple PDAC-specific biomarker candidates: CLDN4, EPCAM, CD151, LGALS3BP, HIST2H2BE, and HIST2H2BF. KRAS mutations in total exosomes were detected in 44.1% of patients undergoing active therapy compared with 73.0% following exosome capture using the selected biomarkers. Enrichment of exosomal cargo was amenable to molecular profiling, elucidating a putative mechanism of resistance to PARP inhibitor therapy in a patient harboring a BRCA2 mutation. Conclusion: Exosomes provide unique opportunities in the context of liquid biopsies for enrichment of tumor-specific material in circulation. We present a comprehensive surfaceome characterization of PDAC exosomes which allows for capture and molecular profiling of tumor-derived DNA.

Association of Single Nucleotide Polymorphisms of Adiponectin Gene with Type 2 Diabetes Mellitus, and Their Influence on Cardiovascular Risk Markers.

Type 2 diabetes mellitus is a genetically heterogeneous condition, characterized by insulin deficiency and/or insulin resistance. The etiology of type 2 diabetes is complex, with involvement of genetic and environmental factors. The adipose tissue protein 'adiponectin' is known to increase insulin sensitivity with decreased risk of type 2 diabetes mellitus. The gene for adiponectin is present on chromosome 3q27, the association of number of single nucleotide polymorphisms of adiponectin gene with type 2 diabetes and its complications have been reported. In the present study the two most common SNPs +45T/G & +276G/T, and their association with type 2 diabetes mellitus and cardiovascular markers were studied. The significant difference in genotype frequencies of +45T/G & +276G/T was found in type 2 diabetic patients and controls, with odds ratio of 1.13 & 1.26 respectively. BMI, Fasting blood glucose, fasting insulin, HOMA IR, triglyceride and VLDL cholesterol levels were increased, and HDL cholesterol level was decreased in patients carrier for +45T/G SNP than the wild type. While only decrease in the HDL cholesterol was reported in carriers for SNP +276G/T than the wild type. The logistic regression analysis revealed the positive association of SNP +45T/G with total cholesterol & LDL cholesterol. And negative association of HDL cholesterol was found with SNPs +45T/G and +276G/T. The haplotype analysis shows the alterations in means of biochemical markers in the patients having haplotype (GG) for mutant allele of SNP +45T/G and wild allele for SNP +276G/T.

Study of Common Genetic Variant S447X in Lipoprotein Lipase and Its Association with Lipids and Lipoproteins in Type 2 Diabetic Patients.

Elevated plasma triglyceride and non-esterified fatty acid concentrations may cause insulin resistance and type 2 diabetes mellitus. Lipoprotein lipase (LPL) is a rate-determining enzyme in lipid metabolism. A variant in the LPL gene has been identified which alters the penultimate amino acid Serine at 447 to a stop codon (S447X), and results in a truncated LPL molecule lacking the C-terminal dipeptide Ser-Gly. The present study was designed to evaluate the frequency of S447X variant in the LPL gene and its effect on the lipid and lipoprotein levels in type 2 diabetic subjects. The genotype frequency distributions of type 2 diabetes patients and controls were in Hardy-Weinberg equilibrium. Comparison of the genotype and allelic frequencies of S447X in subjects with type 2 diabetics compared to controls demonstrated no significant difference. In subjects with type 2 diabetics having hypertriglyceridemia (TG ≥ 150 mg/dl) compared to diabetics with TG level <150 mg/dl, significant difference in genotype frequency was found among these groups, while allelic frequency of X was significantly differed. Logistic regression analysis showed the negative association of LPL S447X variant with TG and VLDL cholesterol, while no association with total cholesterol, HDL cholesterol and LDL cholesterol was found. The lipid levels except for HDL cholesterol were found to be significantly lower in carriers for S447X than wild type in diabetes group. The decreased level of TG and TG rich lipoprotein in subjects with SNP S447X in LPL, predicts anti-atherogenic activity of carriers for S447X variant in general population as well as type 2 diabetic patients.

Arterial blood pressure and vascular function in human saphenous vein.

Hypertension is a risk factor for accelerated saphenous vein (SV) graft disease and endothelial dysfunction in a number of vascular territories. We examined the relationship between blood pressure (BP) and vascular function in SV from 94 male patients undergoing coronary artery bypass grafting (CABG). Patients were pretreated with respect to cholesterol (3.4±1.2 mmol/L) and BP (systolic 139±22 mmHg, diastolic 74±13 mmHg). All patients were taking aspirin, 85% statins, 50% angiotensin-converting enzyme inhibitors and 70% beta-blockers. We demonstrate in human SV rings ex vivo that increased BP has no effect on acetylcholine-mediated vasodilatation (p=0.58), nor on the constrictor response to L-NMMA (p=0.98), but has a positive association with the constrictor response to phenylephrine (p=0.008) and a negative correlation with the vasodilator response to sodium nitroprusside (p=0.03). These results may provide further explanation for the high incidence of early vein graft failure after CABG in hypertensive patients and support an aggressive approach to optimize BP before surgery.

Expression profiling stratifies mesothelioma tumors and signifies deregulation of spindle checkpoint pathway and microtubule network with therapeutic implications.

BACKGROUND: Malignant pleural mesothelioma (MPM) is a lethal neoplasm exhibiting resistance to most treatment regimens and requires effective therapeutic options. Though an effective strategy in many cancer, targeted therapy is relatively unexplored in MPM because the therapeutically important oncogenic pathways and networks in MPM are largely unknown. MATERIALS AND METHODS: We carried out gene expression microarray profiling of 53 surgically resected MPMs tumors along with paired normal tissue. We also carried out whole transcriptomic sequence (RNA-seq) analysis on eight tumor specimens. Taqman-based quantitative Reverse-transcription polymerase chain reaction (qRT-PCR), western analysis and immunohistochemistry (IHC) analysis of mitotic arrest deficient-like 1 (MAD2L1) was carried out on tissue specimens. Cell viability assays of MPM cell lines were carried out to assess sensitivity to specific small molecule inhibitors. RESULTS: Bioinformatics analysis of the microarray data followed by pathway analysis revealed that the mitotic spindle assembly checkpoint (MSAC) pathway was most significantly altered in MPM tumors with upregulation of 18 component genes, including MAD2L1 gene. We validated the microarray data for MAD2L1 expression using quantitative qRT-PCR and western blot analysis on tissue lysates. Additionally, we analyzed expression of the MAD2L1 protein by IHC using an independent tissue microarray set of 80 MPM tissue samples. Robust clustering of gene expression data revealed three novel subgroups of tumors, with unique expression profiles, and showed differential expression of MSAC pathway genes. Network analysis of the microarray data showed the cytoskeleton/spindle microtubules network was the second-most significantly affected network. We also demonstrate that a nontaxane small molecule inhibitor, epothilone B, targeting the microtubules have great efficacy in decreasing viability of 14 MPM cell lines. CONCLUSIONS: Overall, our findings show that MPM tumors have significant deregulation of the MSAC pathway and the microtubule network, it can be classified into three novel molecular subgroups of potential therapeutic importance and epothilone B is a promising therapeutic agent for MPM.

Haemolysis: the harbinger of recurrent mitral regurgitation after mitral valve repair.

We present a case of severe haemolysis post mitral valve repair that presented within the first week of operation. Despite assurance of a good repair, with initial postoperative echocardiographic evidence, the patient subsequently developed haemolysis and required forty units of blood over three months. We emphasize that an unexplained anaemia post mitral valve repair should trigger suspicion for mechanical haemolysis and suggest disease progression or failure of repair.

Apolipoprotein e gene polymorphism and its effect on plasma lipids in arteriosclerosis.

BACKGROUND & OBJECTIVES: Myocardial infarction and stroke are leading causes of death worldwide. Primarily, arteriosclerosis is responsible for these events. There is a strong family history suggesting a genetic cause. Apolipoprotein E (apo E) plays an important role in lipid metabolism. Apo E is polymorphic with three isoforms, ApoE2, ApoE3 and ApoE4; which translate into three alleles of the gene. Its polymorphism may be a risk determinant of atherosclerosis. METHODS: Lipoprotein concentrations were studied, in 100 myocardial infarction and 50 cerebrovascular stroke subjects and compared with age and sex matched controls. Genotypes for apo E isoforms (E2, E3, and E4) for all above subjects and age and sex matched controls were determined by Multiplex Amplification Refractory Mutation System PCR. RESULTS: There were statistically significant higher values of serum total cholesterol and LDL cholesterol in study group, as compared to control group. Study of Apo E isoforms revealed higher proportion of E4 allele in the study group as compared to control group. The occurrence of each allele frequency in study and control group was E4E4: 28.66% and 16.0%, E3E3: 39.33% and 56.66%, E4E3: 14.66% and 9.33%, E3E2: 8.66% and 10.66%, E4E2: 4.66% and 2.66% & for E2E2: 4.0% and 4.66% respectively. INTERPRETATION & CONCLUSION: There were significantly higher levels of serum total cholesterol, LDL cholesterol and triglyceride with E4 allele; when compared with in the study group and between study group and control group. Apo E polymorphism influences serum lipid levels and is an independent risk determinant of arteriosclerosis.

Leptin/adiponectin ratio in patients with coronary heart disease: comparing subjects with and without metabolic syndrome.

BACKGROUND: Adiponectin and leptin are adipose tissue-derived hormones, shown to have opposing associations with the metabolic syndrome and coronary heart disease (CHD). This study evaluated the association between the leptin/adiponectin ratio and the components of the metabolic syndrome in a cohort with CHD. Methods and results This cross-sectional study included data from 105 subjects (men = 91), undergoing first-time elective coronary artery bypass grafting (CABG). Leptin and adiponectin concentrations were determined by enzyme-linked immunosorbent assay (ELISA). Association was found between the leptin/adiponectin ratio and homeostatic model assessment (HOMA) (r(s) = 0.34, P = 0.0006), fasting insulin concentrations (r(s) = 0.37, P = 0.0001), fasting glucose concentrations (r(s) = 0.24, P = 0.01), systolic blood pressure (r(s) = 0.20, P = 0.05), diastolic blood pressure (r(s) = 0.24, P = 0.02), waist circumference (r(s) = 0.55, P < 0.0001), body mass index (BMI) (r(s) = 0.55, P < 0.0001) and waist/hip ratio (r(s) = 0.38, P = 0.0001). A significant difference was found in ratios between those with and without insulin resistance (HOMA > 3 and HOMA ≤ 3) (P = 0.029) and those with and without metabolic syndrome, defined by the International Diabetes Federation, (P < 0.001). However, using receiver operating characteristic (ROC) analysis and assessment of area under curve (AUC), the leptin/adiponectin ratio did not perform significantly better than its components. CONCLUSION: In patients with severe CHD, the leptin/adiponectin ratio was not found to be a robust tool to distinguish patients with and without insulin resistance and those with and without the metabolic syndrome.

Pharmacokinetics of cefpodoxime proxetil with special reference to biochemical parameters, tissue residue, and spermatozoa motility in rats.

BACKGROUND: Cefpodoxime is a semisynthetic third generation cephalosporin analogue with a relatively broader spectrum of antimicrobial activity against gram negative and gram positive organisms. This is attributed to their somewhat increased resistance to degradation by the betalactamase. Cefpodoxime shows good activity against Klebsiella pneumonia, many members of enterobactericeae and almost all strains of Escherichia coli. It is extensively used in human beings against infections caused by susceptible organisms for a prolonged period and even without its judicious indication. Though various researchers have worked on the pharmacokinetic aspects of the drug, its effects on biochemical parameters and spermatozoa activity are scarcely available in literature. AIM: To determine the oral kinetic ( blood and tissue) after single therapeutic dose of cefpodoxime proxetil (20mg/kg oral bid 7 days) in rats of either sex on tissue half life and certain biochemical parameters such as glucose, hemoglobin, protein, ALT, AST and other parameters like tissue residue, sperm count and spermatozoa motility in male rats. MATERIALS AND METHODS: For kinetic studies,24 Wister rats of either sex, 3 months of age, (180-210 gm) were used.(Group I-IV; n=6) Blood samples collected from each animal of Group IV through heart puncture at 0 hour to serve as predrug control. All the group (I-IV) received cefpodoxime proxetil 20 mg/kg once orally as a single dose. At the end of 1,4,12 and 24 hour post oral administration, GroupI,II,III and IVwere utilized for kinetic studies. Blood samples were collected from each animal and vital organs viz brain, lung, liver, spleen, kidney and heart were dissected out for drug analysis and determination of weight. For biochemical parameters, tissue residue and spermatozoa motility, twelve male rats were randomly divided into Groups A and B (n=6) Group B received cefpodoxime (20mg/kg orally bid 7 days) while Group A served as control. Biochemical parameters [Blood glucose, protein, Aspartate transaminase(AST), Alanine transaminase(ALT)and hemoglobin] were measured at 0 and 7 th day while sperm count (total,live and dead)and mean organ weight (study and control group) and tissue residue of drug were evaluated at the end of treatment. Absorption of cefpodoxime was observed at 2 hour and reached a maximum at 4 hour and persisted in blood till 24 hour. Elimination half life in lung was highest followed by heart, liver, kidney and spleen while t½ k in plasma was very low suggesting more affinity of cefpodoxime for tissues than blood. RESULTS AND CONCLUSION: Blood glucose, protein, AST and ALT activities were not significantly altered but the hemoglobin level and total and live sperm count decreased significantly in the study group compared to the control group. Residual level of cefpodoxime was highest in liver followed by kidney and other study organs. Therefore, the drug should be used in human beings judiciously and further study on human subjects is warranted.

All-E lutein and 3'-epilutein in the epidermis of chronic arsenic poisoning.

Identification and quantification of carotenoids in the epidermis of nine patients of chronic arsenic poisoning were done using isocratic reverse phase high performance liquid chromatography (HPLC). The major carotenoids in all the skin biopsies were all-E lutein and 3'-epilutein. Small amount of 2',3'-anhydrolutein, all-E zeaxanthin, and 13-Z zeaxanthin were also present in some of the biopsy samples. Alpha-carotene, beta-carotene, and lycopene were not detected in any sample. The mean (+/- SD) concentration of all-E lutein in the epidermis of healthy volunteers was 1.09 +/- 0.26 microgram/g of wet tissue, whereas it was only 0.29 +/- 0.10 microgram/g in the diffuse dark brown spots of chronic arsenic poisoning. In raindrop-shaped discoloration spots of skin the mean concentration of all-E lutein was 0.86 +/- 0.29 microgram/g of wet tissue. The difference between the concentrations of all-E lutein in the epidermis of healthy volunteers versus patients was for the diffuse dark brown spots statistically significantly (p < 0.05) lower, while this was not significant for the raindrop-shaped discoloration spots. This study suggests that arsenic exposure reduces the number, as well as concentrations of, carotenoids in skin.

Effect of fat distribution on endothelial-dependent and endothelial-independent vasodilatation in healthy humans.

AIM: The present study aims to explore the relationship between inflammatory cytokines, plasma lipids, insulin, blood pressure (BP), total adiposity/markers of fat distribution and endothelial function in healthy people across a wide range of body fatness. METHODS: Seventy-three healthy people (44 women; age range: 24-64 years) with body mass index (BMI) range of 18.6-73.1 kg/m2 were recruited. All participants underwent assessment of conduit artery endothelial-dependent vasodilatation by using flow-mediated vasodilatation (FMD) of the brachial artery and endothelial-independent vasodilatation to sublingual GTN. They had blood taken for measurement of plasma markers of glucose homeostasis (fasting insulin and glucose), systemic inflammation (interleukin-6 (IL-6), C-reactive protein (CRP) and tumour necrosis factor-alpha receptor 2 (TNF-alpha R2)) and lipids (low-density lipoprotein (LDL), high-density lipoprotein (HDL) and triglycerides). Morphometric assessment (waist circumference, BMI and waist-to-hip ratio (WHR)) and systolic and diastolic arterial pressure were also measured. RESULTS: Markers of total body fat/fat distribution (waist circumference, BMI and WHR), inflammation (IL-6, CRP and TNF-alpha R2), metabolism (fasting insulin, HDL, LDL and triglycerides) and BP (systolic and diastolic) correlated with FMD. Among these measurements, WHR was the only independent predictor of FMD (r2 = 0.30; p = 0.0001). CONCLUSIONS: WHR is an important marker of endothelial dysfunction in healthy people across a wide range of body fatness.

Childhood asthma predisposes to spontaneous pneumomediastinum.

Spontaneous pneumomediastinum is a rare condition for which potentially life threatening differential diagnoses must be excluded. A case is presented of a young man with a history of severe childhood asthma, who was successfully treated conservatively.

Traumatic cardiogenic shock due to massive air embolism. A possible role for cardiopulmonary bypass.

Systemic arterial embolism is a potentially lethal complication of bronchopulmonary venous fistula in trauma patients with blunt chest trauma or isolated penetrating lung injury on positive pressure ventilation. A high index of suspicion, early diagnosis and management in specialized centres are keys to a successful outcome.