Postpartum maternal tachycardia - diagnostic pitfalls!

PURPOSE OF REVIEW: Maternal tachycardia is a common sign with a multitude of causes. We attempt to look at the most common sinister ones in the postpartum period. RECENT FINDINGS: Current guidelines differ in the definition of maternal tachycardia. It has been associated with adverse outcomes such as increased length of stay as well as higher mortality if there is underlying peripartum cardiomyopathy. Some recent studies look at common investigations and how these apply to peripartum women, such as ECG markers of arrhythmogenesis, reference ranges for PCT and echocardiogram findings during pregnancy prior to diagnosis of peripartum cardiomyopathy. SUMMARY: Physiological changes make it difficult to interpret maternal tachycardia and thus how best to manage it. We propose the idea of a three-step approach for the assessment of patients, aiming to identify causes including tachyarrhythmias, obstetric haemorrhage, sepsis, venous thromboembolism and peripartum cardiomyopathy.The first step 'BEDSIDE' applies to all patients looking at observations, history and examination. The second step 'BASIC', applies to most patients and covers ECG and basic blood tests. The final step 'EXTRA' assesses the need for further investigations including additional blood tests and imaging. By using this model, clinicians and healthcare professionals should be able to rationalise the need for more invasive investigations whilst maintain good high-quality care.

Dual PI3Kδγ inhibition demonstrates potent anticancer effects in diffuse large B-cell lymphoma models: Discovery and preclinical characterization of LL-00084282.

Phosphoinositide 3-kinase (PI3K) pathway mediates key signaling events downstream to B-cell receptor (BCR) for survival of mature B-cells, and overexpression or overactivation of PI3Kδ is crucial for B-cell malignancies such as diffuse large B-cell lymphoma (DLBCL). Small molecule PI3Kδγ inhibitors, with a known potential to reduce activated B-cell (ABC)-DLBCL transformation, form an important class of therapeutics approved for follicular lymphoma (FL), chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL). In this study, we describe discovery of a potent, selective and efficacious dual PI3Kδγ inhibitor, LL-00084282, having a differentiated efficacy profile in human ABC- and germinal center B-cell (GCB)-DLBCL cell lines. LL-00084282 displayed high potency and superior PI3Kδγ engagement with excellent selectivity over other PI3K isoforms at both IC50/90 concentrations in biochemical and cell-based assays. In contrast to selective PI3Kδ inhibitors, LL-00084282 showed superior and potent anticancer activity in both ABC- and GCB-DLBCL cell lines. LL-00084282 demonstrated in-vivo efficacy in OCI-Ly10 and SU-DHL-6 xenografts with good tolerability. Furthermore, LL-00084282 inhibited pro-inflammatory cytokine secretion and reduced basophil activation in human PBMCs, showing potential implications in immunoinflammatory conditions. Good pharmacokinetic properties in higher species and desirable efficacy profile highlights potential of this novel PI3Kδγ inhibitor for further clinical evaluation in DLBCL patients.

LL-00066471, a novel positive allosteric modulator of α7 nicotinic acetylcholine receptor ameliorates cognitive and sensorimotor gating deficits in animal models: Discovery and preclinical characterization.

α7 nicotinic acetylcholine receptor (α7 nAChR) is an extensively validated target for several neurological and psychiatric conditions namely, dementia and schizophrenia, owing to its vital roles in cognition and sensorimotor gating. Positive allosteric modulation (PAM) of α7 nAChR represents an innovative approach to amplify endogenous cholinergic signaling in a temporally restricted manner in learning and memory centers of brain. α7 nAChR PAMs are anticipated to side-step burgeoning issues observed with several clinical-stage orthosteric α7 nAChR agonists, related to selectivity, tolerance/tachyphylaxis, thus providing a novel dimension in therapeutic strategy and pharmacology of α7 nAChR ion-channel. Here we describe a novel α7 nAChR PAM, LL-00066471, which potently amplified agonist-induced Ca2+ fluxes in neuronal IMR-32 neuroblastoma cells in a α-bungarotoxin (α-BTX) sensitive manner. LL-00066471 showed excellent oral bioavailability across species (mouse, rat and dog), low clearance and good brain penetration (B/P ratio > 1). In vivo, LL-00066471 robustly attenuated cognitive deficits in both procognitive and antiamnesic paradigms of short-term episodic and recognition memory in novel object recognition task (NORT) and social recognition task (SRT), respectively. Additionally, LL-00066471 mitigated apomorphine-induced sensorimotor gating deficits in acoustic startle reflex (ASR) and enhanced antipsychotic efficacy of olanzapine in conditioned avoidance response (CAR) task. Further, LL-00066471 corrected redox-imbalances and reduced cortico-striatal infarcts in stroke model. These finding together suggest that LL-00066471 has potential to symptomatically alleviate cognitive deficits associated with dementias, attenuate sensorimotor gating deficits in schizophrenia and correct redox-imbalances in cerebrovascular disorders. Therefore, LL-00066471 presents potential for management of cognitive impairments associated with neurological and psychiatric conditions.

Discovery of a Potent and Selective PI3Kδ Inhibitor (S)-2,4-Diamino-6-((1-(7-fluoro-1-(4-fluorophenyl)-4-oxo-3-phenyl-4H-quinolizin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile with Improved Pharmacokinetic Profile and Superior Efficacy in Hematological Cancer Models.

PI3Kδ inhibitors have been approved for B-cell malignancies like CLL, small lymphocytic lymphoma, and so forth. However, currently available PI3Kδ inhibitors are nonoptimal, showing weakness against at least one of the several important properties: potency, isoform selectivity, and/or pharmacokinetic profile. To come up with a PI3Kδ inhibitor that overcomes all these deficiencies, a pharmacophoric expansion strategy was employed. Herein, we describe a systematic transformation of a "three-blade propeller" shaped lead, 2,3-disubstituted quinolizinone 11, through a 1,2-disubstituted quinolizinone 20 to a novel "four-blade propeller" shaped 1,2,3-trisubstituted quinolizinone 34. Compound 34 has excellent potency, isoform selectivity, metabolic stability across species, and exhibited a favorable pharmacokinetic profile. Compound 34 also demonstrated a differentiated efficacy profile in human germinal center B and activated B cell-DLBCL cell lines and xenograft models. Compound 34 qualifies for further evaluation as a candidate for monotherapy or in combination with other targeted agents in DLBCLs and other forms of iNHL.

Discovery of isoquinolinone and naphthyridinone-based inhibitors of poly(ADP-ribose) polymerase-1 (PARP1) as anticancer agents: Structure activity relationship and preclinical characterization.

The exploitation of GLU988 and LYS903 residues in PARP1 as targets to design isoquinolinone (I & II) and naphthyridinone (III) analogues is described. Compounds of structure I have good biochemical and cellular potency but suffered from inferior PK. Constraining the linear propylene linker of structure I into a cyclopentene ring (II) offered improved PK parameters, while maintaining potency for PARP1. Finally, to avoid potential issues that may arise from the presence of an anilinic moiety, the nitrogen substituent on the isoquinolinone ring was incorporated as part of the bicyclic ring. This afforded a naphthyridinone scaffold, as shown in structure III. Further optimization of naphthyridinone series led to identification of a novel and highly potent PARP1 inhibitor 34, which was further characterized as preclinical candidate molecule. Compound 34 is orally bioavailable and displayed favorable pharmacokinetic (PK) properties. Compound 34 demonstrated remarkable antitumor efficacy both as a single-agent as well as in combination with chemotherapeutic agents in the BRCA1 mutant MDA-MB-436 breast cancer xenograft model. Additionally, compound 34 also potentiated the effect of agents such as temozolomide in breast cancer, pancreatic cancer and Ewing's sarcoma models.

Tetrameric architecture of an active phenol-bound form of the AAA+ transcriptional regulator DmpR.

The Pseudomonas putida phenol-responsive regulator DmpR is a bacterial enhancer binding protein (bEBP) from the AAA+ ATPase family. Even though it was discovered more than two decades ago and has been widely used for aromatic hydrocarbon sensing, the activation mechanism of DmpR has remained elusive. Here, we show that phenol-bound DmpR forms a tetramer composed of two head-to-head dimers in a head-to-tail arrangement. The DmpR-phenol complex exhibits altered conformations within the C-termini of the sensory domains and shows an asymmetric orientation and angle in its coiled-coil linkers. The structural changes within the phenol binding sites and the downstream ATPase domains suggest that the effector binding signal is propagated through the coiled-coil helixes. The tetrameric DmpR-phenol complex interacts with the σ54 subunit of RNA polymerase in presence of an ATP analogue, indicating that DmpR-like bEBPs tetramers utilize a mechanistic mode distinct from that of hexameric AAA+ ATPases to activate σ54-dependent transcription.

General anaesthesia during caesarean sections: implications for the mother, foetus, anaesthetist and obstetrician.

PURPOSE OF REVIEW: A general anaesthetic is usually given for an emergency caesarean section (Category 1), where there is imminent threat to the mother or foetus. There are many risks in performing a general anaesthetic. The aim of this review is to highlight the effects and risks to the mother and foetus of each step of a general anaesthetic. RECENT FINDINGS: Anaesthetic techniques are changing, and the traditional mantra of using a general anaesthetic for an emergency caesarean sections is being challenged. There are also multiple potential risks of a general anaesthetic that are being better defined. This ranges from awareness during surgery, through to foetal and maternal risks of complications. SUMMARY: This review will outline the different stages of a general anaesthetic and highlight the risks. This summary will allow a better understanding of anaesthetic risks. This will allow obstetricians to have a more informed conversation with an anaesthetist as to form of anaesthetic required (general anaesthetic versus spinal or epidural top-up). The review will also allow obstetricians to give more informed consent to mothers and be aware of the postoperative risks.

Mutation profile in Indian primary myelofibrosis patients and its clinical implications.

BACKGROUND: Primary myelofibrosis (PMF) is a myeloproliferative neoplasm (MPN) characterized by abnormal proliferation of megakaryocytes, bone marrow fibrosis, and extramedullary hematopoiesis. We did mutation profile of 50 patients of PMF and tried to correlate it with initial clinical presentation of these patients. MATERIALS AND METHODS: All new and follow up patients who were diagnosed as PMF based on WHO 2016 definition of PMF were included. Mutation profile of these patients including JAK2 V617F, JAK2 exon 12, CALR and MPL mutations was done and all clinical, demographic and laboratory details were recorded. RESULTS: Total 50 patients were enrolled out of which 29 were males and 21 were females. Out of these patients, 32 (64%) were JAK2 positive, 13 (26%) were CALR positive, 1 (2%) were MPL positive and 4 (8%) were triple negative. As compared to JAK2+ve patients and triple negative group, CALR positive patients were younger, had lower total leucocyte count, larger spleen size, lower dynamic international prognostic scoring system (DIPSS) score and higher grade of fibrosis of marrow. CONCLUSION: This study depicts that incidence of JAK2 and CALR mutations in Indian PMF patients is fairly similar to that in rest of the world. CALR positive patients have better clinical parameters at presentation and have better prognosis as compared to JAK2 positive patients.

Giant cell tumor of soft tissues of low malignant potential: A rare diagnosis on fine needle aspiration cytology.

Primary giant cell tumors of soft tissues (GCT-ST) are extremely rare soft tissue tumors, located in both superficial and deep soft tissues. They resemble osseous giant cell tumors morphologically and immunohistochemically. The tumor exhibits strong positive immunoreactivity for cluster of differentiation 68 (CD68) within multinucleated osteoclast-like giant cells and focal staining of mononuclear cells. Case reports describing the cytohistological features of this entity are very few. We report a case of GCT-ST of low malignant potential diagnosed on fine needle aspiration (FNA) and confirmed on histological and immunohistochemical studies.

Wiskott-Aldrich Syndrome Presenting with JMML-Like Blood Picture and Normal Sized Platelets.

Objective. The aim of this paper is to report the case of Wiskott-Aldrich syndrome (WAS) that presented with unusual laboratory features. Clinical Presentation and Intervention. Male neonate admitted with symptoms related to thrombocytopenia, whose initial diagnosis was considered as neonatal alloimmune thrombocytopenia and JMML (juvenile myelomonocytic leukemia) but subsequently diagnosis was confirmed as WAS. Conclusion. This case shows that a suspicion of WAS is warranted in the setting of neonatal thrombocytopenia with JMML-like blood picture and normal sized platelets.

Undivided attention improves postoperative anesthesia handover recall.

BACKGROUND: For years, undivided attention during the presurgical "timeout" has been utilized as a precaution to ensure patient safety. The information relayed during the timeout is presented in a confirmatory nature rather than a delegation of new information. However, it is a standard of practice in which all members of the operating theater provide their full and undivided attention. Standards of patient care should be contiguous throughout the preoperative, perioperative, and postoperative stages of surgery. In this manner, it is expected that the same undivided attention afforded during the timeout should be maintained when transferring the patient to the postanesthesia care unit. METHODS: In this study, information was collected regarding handover of information during the transfer status postsurgical procedures. Data were collected via observing interactions between the anesthesiologist and the nurse during verbal patient transfers. RESULTS: This study demonstrated that the presence of undivided attention during the handover of a surgical patient in the postanesthesia care unit has a direct correlation with improved recall of the information discussed during handover. CONCLUSION: Focus is on the quantity of information that can be recalled by the transferring nurse, and whether or not undivided attention affects the outcome. Analysis focuses on suggestions to better improve patient safety and recovery when being transferred in an anesthetic setting. The practice of patient handover should be standardized to better improve the safety and quality of medical care.

Identification and Validation of Expressed Sequence Tags from Pigeonpea (Cajanus cajan L.) Root.

Pigeonpea (Cajanus cajan (L) Millsp.) is an important food legume crop of rain fed agriculture in the arid and semiarid tropics of the world. It has deep and extensive root system which serves a number of important physiological and metabolic functions in plant development and growth. In order to identify genes associated with pigeonpea root, ESTs were generated from the root tissues of pigeonpea (GRG-295 genotype) by normalized cDNA library. A total of 105 high quality ESTs were generated by sequencing of 250 random clones which resulted in 72 unigenes comprising 25 contigs and 47 singlets. The ESTs were assigned to 9 functional categories on the basis of their putative function. In order to validate the possible expression of transcripts, four genes, namely, S-adenosylmethionine synthetase, phosphoglycerate kinase, serine carboxypeptidase, and methionine aminopeptidase, were further analyzed by reverse transcriptase PCR. The possible role of the identified transcripts and their functions associated with root will also be a valuable resource for the functional genomics study in legume crop.

Fine-needle aspiration cytology of recurrent epithelioid sarcoma of the foot: Role of immonocytochemistry in definitive diagnosis.

Fine-needle aspirations (FNA) have played a crucial role in the diagnosis and follow-up of malignancies including sarcomas. However, relatively low specificity in the classification of sarcoma is the main limitation of FNA. Epithelioid sarcoma is a rare tumor of soft tissues. Very few individual case reports describing cytological features of epithelioid sarcoma have been documented in the literature. Here, we describe cytological features of epithelioid sarcoma with immunocytohistological correlation.