Head nodding: An unusual presentation of congenital brain tumor

Congenital brain tumors (CBTs) in neonates are defined as tumors presenting within 60 days after birth. Teratoma is the most common type of CBT. A 37-day-old baby was presented to pediatric emergency with complaints of difficulty in breathing, refusal of feed, and lethargy. The baby had continuous head nodding, drooling of saliva, and slight hypotonia of lower limbs which mother, then confirmed, was present since birth. There was a history of admission to another hospital with similar complaints at day 15 of life, where the child was discharged after 5 days of hospitalization with a diagnosis of nasal block. Magnetic resonance imaging brain showed a large mass located centrally suggestive of either pilocytic astrocytoma or medulloblastoma. The patient expired after 6 months in a private hospital. The present case report aims to focuse the importance of an early diagnosis based on the clinical presentation and imaging studies followed by timely intervention which is critical as the prognosis is very poor

To study the clinicoetiological profile of children admitted with bleeding diathesis

 Background: Bleeding complications in children may be caused by disorders of secondary hemostasis or fibrinolysis. A child who presents with bleeding warrants evaluation for a significant bleeding problem. Objectives: The aim is to study the clinicoetiological profile of children admitted with bleeding diathesis. Materials and Methods: Children up to the age of 14 years presenting in the Department of Pediatrics, Pandit B D Sharma Postgraduate Institute of Medical Sciences, Rohtak, with hemorrhagic diathesis, that is, non-traumatic spontaneous bleeding, suspected to be either due to the defective primary hemostatic mechanism (platelet– blood vessel interaction) or defective secondary hemostatic mechanism, were enrolled for this study. Frequency distribution of various bleeding disorders in various age groups was studied. Results: A total of 92 children up to the age of 14 years were taken up for study, of which, maximum cases with bleeding presented with hematemesis (23.9%) followed by melena (22.8%). A total of 73 children (79.34%) presented with skin and joint bleeds. We were able to make diagnosis in 82 children (89.1%). Among 82 patients, 31 (37.8%) had bleeding secondary to infections, 11 (13.4%) had coagulation disorder, 9 (10.97%) had Henoch–Schonlein purpura (HSP) and immune thrombocytopenic purpura (ITP) each, 6 (7.3%) had hypoplastic bone marrow, 2 (2.4%) had chronic malaria, 4 (4.9%) had leukemia, 6 (7.3%) had liver diseases, and 6 (7.3%) had hemorrhagic disease of newborn (HDN). Almost half of the children with bleeding manifestations in each age group had thrombocytopenia. The most common causes of bleeding in <1 year were septicemia with thrombocytopenia and HDN; among 1-7 years were infections, ITP, and coagulation disorders; and in more than 7 years were HSP, ITP, liver disease, and hemolytic-uremic syndrome. Conclusion: Our study foundthat the gastrointestinal tract was the most common site of bleeding in children presenting with non-traumatic spontaneous bleed, and thrombocytopenia was present in 50% of the cases in each age group. We also found that infections were the most common cause of bleeding in younger children, whereas immunological causes and coagulation disorders predominate in older children. Hence, while evaluating any child with bleeding, age at presentation is also an important parameter to find the etiological diagnosis.&nbsp

To study the clinical profile of children with pleural effusion at a Tertiary Care Center in North India: A prospective study

Introduction: Pleural effusion is the most common manifestation of pleural disorders and is mostly secondary to bacterial infections in children. Aims and Objectives: The primary objective was to study the clinical presentation of pleural effusion in hospitalized children. The secondary objective was to establish the etiology. Methods: A prospective observational study conducted from April 2014 to September 2015. Children >1 month and <14 years diagnosed to have pleural effusion on clinical and radiological examination were included in the study. Data regarding demographic profile, presenting complaints, immunization history, anthropometry, biochemical and radiological investigations, and the outcome of the patients were collected. Results: Seventy-five patients were included in this study. The mean age of the patients was 69.97±48.23 months. Regarding etiology of pleural effusion, it was parapneumonic in 35 (46.6%), empyema in 18 (24%), transudative in 12 (16%), tubercular in 9 (12%), and malignant (non-Hodgkin’s lymphoma) in 1 (1.3%) case. The presenting complaints were fever (82.6%), cough (78.7%), respiratory distress (69.3%), chest pain (36%), and abdominal pain (9.3%). There was no sex predominance. About 16% patients were severely malnourished. Severe anemia was present in 5 (6.7%) patients. None of them required decortication surgery, and none of the patients expired during hospitalization. Conclusion: Pleural effusion is a major health problem with parapneumonic effusion still beingthe most common etiology. Our study also confirmed that fever, cough, and respiratory distress were the most common presenting complaints and most of the children were malnourished. A high index of suspicion is required to avoid delays in diagnosis that may influence treatment and outcome

Mechanism of efficient anti-Markovnikov olefin hydroarylation catalyzed by homogeneous Ir(III) complexes

The mechanism of the hydroarylation reaction between unactivated olefins (ethylene, propylene, and styrene) and benzene catalyzed by [(R)Ir(μ-acac-O,O,C^3)-(acac-O,O)_2]_2 and [R-Ir(acac-O,O)_2(L)] (R = acetylacetonato, CH_3, CH_2CH_3, Ph, or CH_2CH_2Ph, and L = H_2O or pyridine) Ir(III) complexes was studied by experimental methods. The system is selective for generating the anti-Markovnikov product of linear alkylarenes (61 : 39 for benzene + propylene and 98 : 2 for benzene + styrene). The reaction mechanism was found to follow a rate law with first-order dependence on benzene and catalyst, but a non-linear dependence on olefin. ^(13)C-labelling studies with CH_3^(13)CH_2-Ir-Py showed that reversible β-hydride elimination is facile, but unproductive, giving exclusively saturated alkylarene products. The migration of the ^(13)C-label from the α to β-positions was found to be slower than the C–H activation of benzene (and thus formation of ethane and Ph-d_5-Ir-Py). Kinetic analysis under steady state conditions gave a ratio of the rate constants for CH activation and β-hydride elimination (k_(CH): k_β) of 0.5. The comparable magnitude of these rates suggests a common rate determining transition state/intermediate, which has been shown previously with B3LYP density functional theory (DFT) calculations. Overall, the mechanism of hydroarylation proceeds through a series of pre-equilibrium dissociative steps involving rupture of the dinuclear species or the loss of L from Ph-Ir-L to the solvento, 16-electron species, Ph-Ir(acac-O,O)_2-Sol (where Sol refers to coordinated solvent). This species then undergoes trans to cis isomerization of the acetylacetonato ligand to yield the pseudo octahedral species cis-Ph-Ir-Sol, which is followed by olefin insertion (the regioselective and rate determining step), and then activation of the C–H bond of an incoming benzene to generate the product and regenerate the catalyst

Effective Menin inhibitor-based combinations against AML with MLL rearrangement or NPM1 mutation (NPM1c)

Treatment with Menin inhibitor (MI) disrupts the interaction between Menin and MLL1 or MLL1-fusion protein (FP), inhibits HOXA9/MEIS1, induces differentiation and loss of survival of AML harboring MLL1 re-arrangement (r) and FP, or expressing mutant (mt)-NPM1. Following MI treatment, although clinical responses are common, the majority of patients with AML with MLL1-r or mt-NPM1 succumb to their disease. Pre-clinical studies presented here demonstrate that genetic knockout or degradation of Menin or treatment with the MI SNDX-50469 reduces MLL1/MLL1-FP targets, associated with MI-induced differentiation and loss of viability. MI treatment also attenuates BCL2 and CDK6 levels. Co-treatment with SNDX-50469 and BCL2 inhibitor (venetoclax), or CDK6 inhibitor (abemaciclib) induces synergistic lethality in cell lines and patient-derived AML cells harboring MLL1-r or mtNPM1. Combined therapy with SNDX-5613 and venetoclax exerts superior in vivo efficacy in a cell line or PD AML cell xenografts harboring MLL1-r or mt-NPM1. Synergy with the MI-based combinations is preserved against MLL1-r AML cells expressing FLT3 mutation, also CRISPR-edited to introduce mtTP53. These findings highlight the promise of clinically testing these MI-based combinations against AML harboring MLL1-r or mtNPM1

Validation of a noninvasive aMMP-8 point-of-care diagnostic methodology in COVID-19 patients with periodontal disease

Objectives: The aim of this study was to validate an active matrix metalloproteinase (MMP-8) point-of-care diagnostic tool in COVID-19 patients with periodontal disease. Subjects, Materials, and Methods: Seventy-two COVID-19-positive and 30 COVID-19-negative subjects were enrolled in the study. Demographic data were recorded, periodontal examination carried out, and chairside tests run for evaluating the expression of active MMP-8 (aMMP-8) in the site with maximum periodontal breakdown via gingival crevicular fluid sampling as well as via a mouth rinse-based kit for general disease activity. In COVID-19-positive patients, the kits were run again once the patients turned COVID-19 negative. Results: The overall (n = 102) sensitivity/specificity of the mouthrinse-based kits to detect periodontal disease was 79.41%136.76% and that of site-specific kits was 64.71%/55.88% while adjusting for age, gender, and smoking status increased the sensitivity and specificity (82.35%/76.47% and 73.53%/88.24, respectively). Receiver operating characteristic (ROC) analysis for the adjusted model revealed very good area under the ROC curve 0.746-0.869 (p < .001) and 0.740-0.872 (p < .001) (the aMMP-8 mouth rinse and site-specific kits, respectively). No statistically significant difference was observed in the distribution of results of aMMP-8 mouth rinse test (p = .302) and aMMP-8 site-specific test (p = .189) once the subjects recovered from COVID-19. Conclusions: The findings of the present study support the aMMP-8 point-of-care testing (PoCT) kits as screening tools for periodontitis in COVID-19 patients. The overall screening accuracy can be further increased by utilizing adjunctively risk factors of periodontitis. The reported noninvasive, user-friendly, and objective PoCT diagnostic methodology may provide a way of stratifying risk groups, deciding upon referrals, and in the institution of diligent oral hygiene regimens.Peer reviewe

Targeting of epigenetic co-dependencies enhances anti-AML efficacy of Menin inhibitor in AML with MLL1-r or mutant NPM1

Monotherapy with Menin inhibitor (MI), e.g., SNDX-5613, induces clinical remissions in patients with relapsed/refractory AML harboring MLL1-r or mtNPM1, but most patients either fail to respond or eventually relapse. Utilizing single-cell RNA-Seq, ChiP-Seq, ATAC-Seq, RNA-Seq, RPPA, and mass cytometry (CyTOF) analyses, present pre-clinical studies elucidate gene-expression correlates of MI efficacy in AML cells harboring MLL1-r or mtNPM1. Notably, MI-mediated genome-wide, concordant, log2 fold-perturbations in ATAC-Seq and RNA-Seq peaks were observed at the loci of MLL-FP target genes, with upregulation of mRNAs associated with AML differentiation. MI treatment also reduced the number of AML cells expressing the stem/progenitor cell signature. A protein domain-focused CRISPR-Cas9 screen in MLL1-r AML cells identified targetable co-dependencies with MI treatment, including BRD4, EP300, MOZ and KDM1A. Consistent with this, in vitro co-treatment with MI and BET, MOZ, LSD1 or CBP/p300 inhibitor induced synergistic loss of viability of AML cells with MLL1-r or mtNPM1. Co-treatment with MI and BET or CBP/p300 inhibitor also exerted significantly superior in vivo efficacy in xenograft models of AML with MLL1-r. These findings highlight novel, MI-based combinations that could prevent escape of AML stem/progenitor cells following MI monotherapy, which is responsible for therapy-refractory AML relapse