Cannabidiol inhibits SARS-CoV-2 replication through induction of the host ER stress and innate immune responses

The spread of SARS-CoV-2 and ongoing COVID-19 pandemic underscores the need for new treatments. Here we report that cannabidiol (CBD) inhibits infection of SARS-CoV-2 in cells and mice. CBD and its metabolite 7-OH-CBD, but not THC or other congeneric cannabinoids tested, potently block SARS-CoV-2 replication in lung epithelial cells. CBD acts after viral entry, inhibiting viral gene expression and reversing many effects of SARS-CoV-2 on host gene transcription. CBD inhibits SARS-CoV-2 replication in part by up-regulating the host IRE1alpha RNase endoplasmic reticulum (ER) stress response and interferon signaling pathways. In matched groups of human patients from the National COVID Cohort Collaborative, CBD (100 mg/ml oral solution per medical records) had a significant negative association with positive SARS-CoV-2 tests. This study highlights CBD as a potential preventative agent for early-stage SARS-CoV-2 infection and merits future clinical trials. We caution against use of non-medical formulations including edibles, inhalants or topicals as a preventative or treatment therapy at the present time

In Silico Binding of 2-Aminocyclobutanones to SARS-CoV-2 Nsp13 Helicase and Demonstration of Antiviral Activity

The landscape of viral strains and lineages of SARS-CoV-2 keeps changing and is currently dominated by Delta and Omicron variants. Members of the latest Omicron variants, including BA.1, are showing a high level of immune evasion, and Omicron has become a prominent variant circulating globally. In our search for versatile medicinal chemistry scaffolds, we prepared a library of substituted α-aminocyclobutanones from an α-aminocyclobutanone synthon (11). We performed an in silico screen of this actual chemical library as well as other virtual 2-aminocyclobutanone analogs against seven SARS-CoV-2 nonstructural proteins to identify potential drug leads against SARS-CoV-2, and more broadly against coronavirus antiviral targets. Several of these analogs were initially identified as in silico hits against SARS-CoV-2 nonstructural protein 13 (Nsp13) helicase through molecular docking and dynamics simulations. Antiviral activity of the original hits as well as α-aminocyclobutanone analogs that were predicted to bind more tightly to SARS-CoV-2 Nsp13 helicase are reported. We now report cyclobutanone derivatives that exhibit anti-SARS-CoV-2 activity. Furthermore, the Nsp13 helicase enzyme has been the target of relatively few target-based drug discovery efforts, in part due to a very late release of a high-resolution structure accompanied by a limited understanding of its protein biochemistry. In general, antiviral agents initially efficacious against wild-type SARS-CoV-2 strains have lower activities against variants due to heavy viral loads and greater turnover rates, but the inhibitors we are reporting have higher activities against the later variants than the wild-type (10–20X). We speculate this could be due to Nsp13 helicase being a critical bottleneck in faster replication rates of the new variants, so targeting this enzyme affects these variants to an even greater extent. This work calls attention to cyclobutanones as a useful medicinal chemistry scaffold, and the need for additional focus on the discovery of Nsp13 helicase inhibitors to combat the aggressive and immune-evading variants of concern (VOCs)

CELIAC DISEASE CASE FINDING STRATEGY IN ROMANIAN SYMPTOMATIC CHILDREN

Objectives. Pediatricians face various challenges in different stages of celiac disease (CD) diagnosis. Whom to test is intensely debated because of CD’s heterogenous clinical spectrum. The main purpose of the study was to identify symptoms or symptom associations that should initiate an active strategy of CD early diagnosis in Romanian children. Material and method. We conducted a prospective study in “Grigore Alexandrescu” Emergency Children’s Hospital. From March 2013 until February 2014, 249 children with symptoms/signs at risk of CD were included. Results. CD was diagnosed in 11 (1/21 patients evaluated). One in 12.6; 16; 18; 18.5 and 18.5 children respectively with chronic diarrhea, low stature, growth failure, recurrent abdominal pain and constipation had CD. Certain symptom associations increased the risk: classical symptom associations (chronic diarrhea and weight loss), as well as other associations: recurrent abdominal pain and weight loss, constipation and weight loss, constipation and refractory iron deficiency anemia. Conclusion. Active screening among patients with symptoms and especially symptom associations at risk of CD would improve diagnosis rates in pediatric CD

Spherical nucleic acids as an infectious disease vaccine platform

Despite recent efforts demonstrating that organization and presentation of vaccine components are just as important as composition in dictating vaccine efficacy, antiviral vaccines have long focused solely on the identification of the immunological target. Herein, we describe a study aimed at exploring how vaccine component presentation in the context of spherical nucleic acids (SNAs) can be used to elicit and maximize an antiviral response. Using COVID-19 as a topical example of an infectious disease with an urgent need for rapid vaccine development, we designed an antiviral SNA vaccine, encapsulating the receptor-binding domain (RBD) subunit into a liposome and decorating the core with a dense shell of CpG motif toll-like receptor 9 agonist oligonucleotides. This vaccine induces memory B cell formation in human cells, and in vivo administration into mice generates robust binding and neutralizing antibody titers. Moreover, the SNA vaccine outperforms multiple simple mixtures incorporating clinically employed adjuvants. Through modular changes to SNA structure, we uncover key relationships and proteomic insights between adjuvant and antigen ratios, concepts potentially translatable across vaccine platforms and disease models. Importantly, when humanized ACE2 transgenic mice were challenged in vivo against a lethal live virus, only mice that received the SNA vaccine had a 100% survival rate and lungs that were clear of virus by plaque analysis. This work underscores the potential for SNAs to be implemented as an easily adaptable and generalizable platform to fight infectious disease and demonstrates the importance of structure and presentation in the design of next-generation antiviral vaccines

ISOLATED GROWTH HORMONE DEFICIENCY – A RARE, BUT TREATABLE CAUSE OF LOW STATURE

Growth hormone deficiency is a rare cause of low stature. Early recognition of the disease results in effective treatment, leading to a final height as closely as possible to the genetic target. The authors present the case of a 1 year 2 months old girl admitted for growth evaluation in our department. She had been previously diagnosed with isolated growth hormone deficiency in an Endocrinology Unit and was now sent to complete the investigations and undergo imaging studies. The laboratory investigations excluded other pathologies. The MRI showed adenohypophysis hypoplasia, thin hypophyseal stalk. Se is started on growth hormone substitution treatment with good results

DEFICITUL IZOLAT DE HORMON DE CREŞTERE – CAUZĂ RARĂ, DAR TRATABILĂ DE HIPOSTATURĂ

Deficitul de hormon de creştere este o cauză rară de statură joasă. Recunoaşterea precoce a afecţiunii permite un tratament eficient, ducând la o talie finală cât mai apropiată de talia ţintă genetică. Prezentăm cazul unui copil în vârstă de 1 an şi 2 luni, internat în clinica noastră pentru evaluare staturo-ponderală. Pacienta fusese diagnosticată la vârsta de 1 an cu deficit de hormon de creştere într-o clinică de endocrinologie pediatrică şi a fost îndrumată în clinica noastră pentru completarea investigaţiilor şi excluderea unei patologii structurale hipotalamo-hipofizare. Investigaţiile efectuate au exclus alte cauze de statură joasă. Evaluarea imagistică a evidenţiat hipotrofie adenohipofizară cu tijă hipofizară filiformă. Se îndrumă către clinica de endocrinologie, unde se iniţiază tratament cu hormon de creştere cu evoluţie favorabilă

Evaluation of c677t and a1298c polymorphism of the methylenetetrahydrofolate reductase gene as a maternal risk factor for trisomy 21 (a monocentric study)

Aim: To assess the risk for trisomy 21 in children, depending on the polymorphisms C677T and A1298C of the methylenetetrahydrofolate reductase (MTHFR) gene in mothers

STRATEGIE DE CĂUTARE ACTIVĂ A CAZURILOR DE BOALĂ CELIACĂ LA COPIII SIMPTOMATICI DIN ROMÂNIA

Obiective. Medicii pediatri întâmpină provocări variate în diferite etape ale diagnosticului de boală celiacă (BC) la copil. Pe cine să testăm este în continuare un subiect disputat din cauza tabloului clinic heterogen. Scopul principal al studiului de faţă a fost de a identifica simptome sau asocieri de simptome care ar trebui să ridice suspiciunea şi să iniţieze demersuri pentru diagnostic precoce de BC la copil. Material şi metodă. Am efectuat un studiu prospectiv în cadrul secţiilor de Pediatrie ale Spitalului „Grigore Alexandrescu“, în perioada martie 2013-februarie 2014. Au fost incluşi 249 de copii cu simptome/semne sugestive pentru BC. Rezultate. Au fost diagnosticaţi cu BC 11 pacienţi (1 din 21 de pacienţi evaluaţi). Pentru unul dintre 12,6; 16; 18; respectiv 18,5 dintre copiii cu diaree cronică, hipostatură, deficitul creşterii, dureri abdominale recurente şi constipaţie s-a stabilit diagnosticul de BC. Anumite asocieri de simptome au crescut acest risc: asocieri clasice (diaree cronică şi scădere în greutate), dar şi alte asocieri: dureri abdominale recurente şi scădere în greutate, constipaţie şi scădere în greutate, constipaţie şi anemie persistentă, refractară la tratament. Concluzii. Căutarea activă în rândul pacienţilor cu simptome şi, mai ales, asocieri de simptome la risc de BC ar îmbunătăţi depistarea şi ar creşte frecvenţa cu care este stabilit diagnosticul la copil