Study of clinical profile and management of patients with pulmonary embolism – Single center study

Objective

To study the clinical profile, diagnostic methods and management in patients with symptomatic pulmonary embolism (PE).

Methods

Retrospective assessment of clinical features and management of patients presenting with symptomatic pulmonary embolism from January 2005 to March 2012.

Results

35 patients who were newly diagnosed to have pulmonary embolism with a mean age of 52.1 years were included in the study. Dyspnea (91.4%) and syncope (22.8%) were the predominant symptoms. Echocardiography was done in all patients. 30 patients (85.7%) had pulmonary arterial hypertension, 31 patients (88.5%) had evidence of RV dysfunction and 4 patients (16.7%) had evidence of thrombus in PA, RV. Out of 35 patients, 34 patients (97.14%) showed positive d-dimer reports. Among 35 patients, 24 (68.5%) had positive troponin values. V/Q scan was done in 14 patients (40%) and CT pulmonary angiogram (CTPA) was done in 24 patients (68.5%.). Thrombolysis was done is 24 patients (68.5%). All patients received low molecular weight heparin followed by warfarin. Of the 35 patients, 34 (97.1%) were discharged and were under regular follow up for 6 months and one patient died during the hospital stay.

Conclusion

Pulmonary embolism is a common problem and can be easily diagnosed provided it is clinically suspected. Early diagnosis and aggressive management is the key to successful outcome.     

Two step,one-pot sequential synthesis of functionalized hybrid polyheterocyclic scaffolds via a solid state melt reaction (SSMR)

A new one pot assembly of highly functionalized benzo[a]phenazinone fused chromene/bicyclic scaffolds via a domino Knoevenagel intramolecular hetero-Diels–Alder (IMHDA) strategy using a solid state melt reaction (SSMR) of 2-hydroxynaphthalene 1,4-dione, o-phenylenediamine, O-allyl salicylaldehyde/O-vinyl salicylaldehyde derivatives is reported. The formation of five new bonds (two C–C bonds and three C–O bonds), three six-membered rings, and three stereogenic centers in a one-pot manner is very attractive. Ease of reaction with short time, good yields with water as the only byproduct and work up free procedure are some of the excellent features of the present protocol.

A new one pot assembly of highly functionalized benzo[a]phenazinone fused chromene/bicyclic scaffolds via a domino Knoevenagel intramolecular hetero-Diels–Alder (IMHDA) strategy using a solid state melt reaction (SSMR) is reported.

Multicomponent reactions (MCRs)¹ are known to construct complex structures from simple starting materials in a rapid and highly efficient manner where the production of wastes is minimized. Those multicomponent reactions which are carried out in a ‘one-pot’ MC sequential manner provide a high degree of reaction mass efficiency, which is crucial in the development of modern synthetic methodology for drug discovery and pharmaceutical programs.² Enormous work has been carried out in the field of multicomponent reactions in the past decade where several MCRs have been developed and extensively used in natural product synthesis and drug discovery. The Ugi reaction is a prime example of a four-component reaction that has been found to be a powerful and efficient method for the preparation of α-amino amides both in academia and industry.³ Therefore, the development of new MCRs for the synthesis of biologically active molecules continues to attract considerable attention for their atom- and step economy features.Heterocycles having nitrogen atom are widely available in nature and possess diverse and important biological activities.⁴ Phenazines are a group of organic compounds known to the mankind since past 150 years and are known to exhibit significant biological activities such as antimalarial, fungicidal, trypanocidal, antiplatelet, etc.⁵ A large number of drug molecules bearing the phenazine scaffold have been designed and evaluated in the recent years. The phenazines motif possess two dentate N atoms with three fused aromatic rings and an electron deficient conjugated system. The presence of the above features in phenazines give them an ability to form hydrogen bonds, ionic bonds, and π–π interactions with relative ease, and their use has also been demonstrated in supramolecular chemistry for molecular recognition (MR), supramolecular self-assembly (MS-A), and organic optic electronics materials.⁶ Few representative examples of phenazine and its derivatives are shown in the Fig. 1.Open in a separate windowFig. 1Some of naturally occurring phenazine derivatives.Chromenes and their derivatives are privileged scaffolds due to their ubiquitous presence in many natural products and synthetic molecules.⁷ Chromenes are also an important class of compounds displaying interesting biological activities against prostate cancer (DU-145) and breast cancer (MCF-7).⁸ Additionally, they have medicinal qualities such as antiviral and antimicrobial activity.⁹ Chromenes have also found their use in medicine, health-promoting agents, and photochromic materials.¹⁰In recent years, the domino-Knoevenagel-hetero-Diels–Alder reaction (DKHDA) which was extensively studied by Tietze''s group constitutes an important process for the preparation of complex compounds having interesting biological properties.¹¹ The Diels–Alder reaction is important since it allows the formation of functionalized rings where there is complete control on regio-, diastereo-, and enantioselectivity. Moreover, the concerted nature of the Diels–Alder reactions allow the selective formation of up to three stereogenic centers in a single reaction step. Majority of the reactions reported on DKHDA have utilized 1,3-dicarbonyl compounds such as dimethyl barbituric acid, Meldrum''s acid and 1,3-indanedione.¹² Additionally, other active methylene compounds like 1-phenyl-3-methyl pyrazolone, 4-hydroxy-coumarin, dihydroindole-2-thione, benzoylacetonitrile, 4-hydroxydithiocoumarin have been also used;¹³ but phenazinones have never been employed in DKHDA reactions. To the best of our knowledge, there are no reports on intramolecular DKHDA reactions using phenazinone as the coupling partner. Due to our interest in the construction of bioactive fused chromenophenazinone derivatives and since this molecule contains a 1,3-dicarbonyl as well as a 1,3-imine moiety, it would be very challenging to control the regioselectivity of the molecule; therefore phenazinone scaffold can act as a model substrate for an intramolecular DKHDA. We envisaged that a series of angular polycyclic chromeno fused phenazinone derivatives could be obtained and it is possible that the final hybrid compounds will result in being more selective and efficient than chromene and phenazinone compounds in biological assays.In this direction, we have decided to develop a new method for the preparation of novel benzo[a]phenazinone fused chromene/bicyclic scaffolds via a domino Knoevenagel intramolecular hetero-Diels–Alder (IMHDA) strategy using a solid state melt reaction (SSMR). As part of our research program for the development of new synthetic methods in heterocyclic chemistry¹⁴ and solid state melt reactions,^15,16 we would like to report a simple and a general domino three-component reaction of 2-hydroxynaphthalene-1,4-dione, o-phenylenediamine and O-allylated/vinylated salicylaldehyde for the synthesis of pentacyclic benzo[a]phenazinone fused chromene/bicyclic scaffolds under environmentally benign reaction conditions (Scheme 1).Open in a separate windowScheme 1Synthetic approach to benzo[a]phenazinone fused chromenes.We have started this study by melting 2-hydroxynaphthalene-1,4-dione (2), o-phenylenediamine (1), and (E)-methyl 2-((2-formylphenoxy)methyl)-3-phenylacrylate (3) at 180 °C for 1 h in solvent free condition. Unfortunately, we could not obtain any desired product and the formation of a complex mixture was observed. To minimize the formation of the side products, the 2-hydroxynaphthalene-1,4-dione (2) and o-phenylenediamine (1) were first melted at 180 °C for 10 minutes to form the intermediate benzo[a]phenazin-5-ol. Subsequently, (E)-methyl 2-((2-formylphenoxy)methyl)-3-phenylacrylate 3a was added and the mixture was melted under the same temperature for 1 h which afforded the desired hybrid product chromene fused benzo[a]phenazinone 4a (ester moiety in ring junction) in 78% yield as shown in

Rationale and design of “Can Very Low Dose Rivaroxaban (VLDR) in addition to dual antiplatelet therapy improve thrombotic status in acute coronary syndrome (VaLiDate-R)” study

Impaired endogenous fibrinolysis is novel biomarker that can identify patients with ACS at increased cardiovascular risk. The addition of Very Low Dose Rivaroxaban (VLDR) to dual antiplatelet therapy has been shown to reduce cardiovascular events but at a cost of increased bleeding and is therefore not suitable for all-comers. Targeted additional pharmacotherapy with VLDR to improve endogenous fibrinolysis may improve outcomes in high-risk patients, whilst avoiding unnecessary bleeding in low-risk individuals. The VaLiDate-R study (ClinicalTrials.gov Identifier: NCT03775746, EudraCT: 2018-003299-11) is an investigator-initiated, randomised, open-label, single centre trial comparing the effect of 3 antithrombotic regimens on endogenous fibrinolysis in 150 patients with ACS. Subjects whose screening blood test shows impaired fibrinolytic status (lysis time?>?2000s), will be randomised to one of 3 treatment arms in a 1:1:1 ratio: clopidogrel 75 mg daily (Group 1); clopidogrel 75 mg daily plus rivaroxaban 2.5 mg twice daily (Group 2); ticagrelor 90 mg twice daily (Group 3), in addition to aspirin 75 mg daily. Rivaroxaban will be given for 30 days. Fibrinolytic status will be assessed during admission and at 2, 4 and 8 weeks. The primary outcome measure is the change in fibrinolysis time from admission to 4 weeks follow-up, using the Global Thrombosis Test. If VLDR can improve endogenous fibrinolysis in ACS, future large-scale studies would be required to assess whether targeted use of VLDR in patients with ACS and impaired fibrinolysis can translate into improved clinical outcomes, with reduction in major adverse cardiovascular events in this high-risk cohort.

     

Biology of sepsis: Its relevance to pediatric nephrology

Because of its multi-organ involvement, the syndrome of sepsis provides clinical challenges to a wide variety of health care providers. While multi-organ dysfunction triggered by sepsis requires general supportive critical care provided by intensivists, the impact of sepsis on renal function and the ability of renal replacement therapies to modulate its biologic consequences provide a significant opportunity for pediatric nephrologists and related care providers to impact outcomes. In this review, we aim to highlight newer areas of understanding of the pathobiology of sepsis with special emphasis on those aspects of particular interest to pediatric nephrology. As such, we aim to: (1) review the definition of sepsis and discuss advances in our mechanistic understanding of sepsis; (2) review current hypotheses regarding sepsis-induced acute kidney injury (AKI) and describe its epidemiology based on evolving definitions of AKI; (3) review the impact of renal failure on the immune system, highlighting the sepsis risk in this cohort and strategies that might minimize this risk; (4) review how renal replacement therapeutic strategies may impact sepsis-induced AKI outcomes. By focusing the review on these specific areas, we have omitted other important areas of the biology of sepsis and additional interactions with renal function from this discussion; however, we have aimed to provide a comprehensive list of references that provide contemporary reviews of these additional areas.     

Two Body Wear of Newly Introduced Nanocomposite Teeth and Cross Linked Four Layered Acrylic Teeth: a Comparitive In Vitro Study

Statement of Problem: Wear of complete denture teeth results in compromise in denture esthetics and functions. To counteract this problem, artificial teeth with increased wear resistance had been introduced in the market such as nanocomposite teeth. Purpose: The purpose of this study was to compare the amount of wear between nanocomposite teeth and acrylic teeth. Materials and methods: Fifteen specimens were chosen from each group namely the nanocomposite teeth (SR_-PHONARES) and the acrylic teeth (ACRY PLUS). Maxillary premolar was only chosen for testing and the samples were customized according to the specifications of the pin on disc machine. Pin on disc machine is a two body tribometer which quantifies the amount of wear under a specific load and time. Test samples were mounted on to the receptacle of the pin on disc machine and tested under a load of 0.3 kg for 1,000 cycles of rotation against a 600 grit emery paper. The amount of wear is displayed from the digital reading obtained from the pin on disc machine. Results: After statistical analysis, it was found that, the amount of wear is more in four layered acrylic teeth. The p value obtained is 0.002 (<0.005) thus implies that the difference in wear between nanocomposite teeth and acrylic teeth is statistically significant. Conclusion: Though the nanocomposite teeth has less amount of wear than the four layered acrylic teeth, the difference is very less and adds only to a little clinical significance but the cost of the nanocomposite is four times that of the acrylic teeth. Further clinical studies must be performed to confirm our results.     

Icicle sign: autoimmune pancreatitis

Abdominal Radiology -     

TCCA-mediated oxidative rearrangement of tetrahydro-β-carbolines: facile access to spirooxindoles and the total synthesis of (±)-coerulescine and (±)-horsfiline

Multi-reactive centered reagents are beneficial in chemical synthesis due to their advantage of minimal material utilization and formation of less by-products. Trichloroisocyanuric acid (TCCA), a reagent with three reactive centers, was employed in the synthesis of spirooxindoles through the oxidative rearrangement of various N-protected tetrahydro-β-carbolines. In this protocol, low equivalents of TCCA were required to access spirooxindoles (up to 99% yield) with a wide substrate scope. Furthermore, the applicability and robustness of this protocol were proven for the gram-scale total synthesis of natural alkaloids such as (±)-coerulescine (1) and (±)-horsfiline (2) in excellent yields.

Three-reactive centered reagent (TCCA) mediated construction of spirooxindoles through an oxidative rearrangement of various N-protected tetrahydro-β-carbolines and total synthesis of natural alkaloids (±)-coerulescine and (±)-horsfiline.