Exploring cyclopropylamine containing cyanopyrimidines as LSD1 inhibitors: Design, synthesis, ADMET, MD analysis and anticancer activity profiling.

In this series we report the structure-based design, synthesis and anticancer activity evaluation of a series of eighteen cyclopropylamine containing cyanopyrimidine derivatives. The computational predictions of ADMET properties revealed appropriate aqueous solubility, high GI absorption, no BBB permeability, no Lipinski rule violations, medium total clearance and no mutagenic, tumorigenic, irritant and reproductive toxic risks for most of the compounds. Compounds VIIb, VIIi and VIIm emerged as the most potent anticancer agents among all compounds evaluated against 60 cancer cell lines through the one-dose (10 µM) sulforhodamine B assay. Further, the multiple dose cell viability studies against cancer cell lines MOLT-4, A549 and HCT-116 revealed results consistent with the one-dose assay, besides sparing normal cell line HEK-293. The three potent compounds also displayed potent LSD1 inhibitory activity with IC50 values of 2.25, 1.80 and 6.08 µM. The n-propyl-thio/isopropyl-thio group bonded to the pyrimidine ring and unsubstituted/ electron donating group (at the para- position) attached to the phenyl ring resulted in enhanced anticancer activity. However, against leukemia cancer, the electron donating isopropyl group remarkably enhanced anti-cancer activity. Our findings provide important leads, which merit further optimization to result in better cancer therapeutics.

Synthesis, in-Silico studies and biological evaluation of pyrimidine based thiazolidinedione derivatives as potential anti-diabetic agent.

Despite the advancements in the management of Diabetes mellitus, the design and synthesis of drug molecule which ameliorates the hyperglycemia and associated secondary complications in diabetic patients, still remains a challenge. Herein, we report the synthesis, characterization and anti-diabetic evaluation of pyrimidine-thiazolidinedione derivatives. The synthesized compounds were characterized by 1H NMR, 13C NMR, FTIR and Mass Spectroscopic analytical techniques. The in-silico ADME studies depicted that the compounds were within the permissible limits of the Lipinski's rule of five. The compounds 6e and 6m showing the best results in OGTT were evaluated for in-vivo anti-diabetic evaluation in STZ induced diabetic rats. Administration of 6e and 6m for four weeks decreased the blood glucose levels significantly. Compound 6e (4.5 mg/kg p.o.) was the most potent compound of the series. It reduced the level of blood glucose to 145.2 ± 1.35 compared to the standard Pioglitazone (150.2 ± 1.06). Moreover, the 6e and 6m treated group did not show increase in bodyweight. The biochemical estimations showed that the levels of ALT, ASP, ALP, urea, creatinine, blood urea nitrogen, total protein and LDH restored to normal in 6e and 6m treated groups as compared to STZ control group. The histopathological studies supported the results obtained in biochemical estimations. Both the compounds did not show any toxicity. Moreover, the histopathological studies of pancreas, liver, heart and kidney revealed that the structural integrity of these tissues restored to almost normal in 6e and 6m treated groups as compared to STZ control group. Based upon these findings it can be concluded that the pyrimidine-based thiazolidinedione derivatives represent novel anti-diabetic agents with least side effects.

Effectiveness of estrogen and its derivatives over dexamethasone in the treatment of COVID-19.

Coronavirus disease (COVID-19) is an infectious disease caused by the SARS-CoV-2 virus and dexamethasone is a glucocorticoid widely used for its treatment. Dexamethasone is not used in non-severe cases due to its immunosuppressant action. So, considering this, Estrogen and Estetrol were tested for the treatment of COVID-19 as they all possess a common steroid ring and dislike dexamethasone, they are immunoenhancer. Virtual screening of test ligands was performed through molecular docking, MM-GBSA, simulations, in silico ADMET and drug-likeness prediction to identify their potential to inhibit the effects of SARS-CoV-2. Results showed that test ligands possess drug-like properties and they are safe as drug candidates. The protein-ligand interaction study revealed that they bind with the amino acid residues at the active site of the target proteins and the test ligands possess better binding potential than Dexamethasone. With protein Mpro, Estetrol and Estrogen showed docking score of -7.240 and -5.491 kcal/mol, and with protein ACE2, Estetrol and Estrogen showed docking score of -5.269 and -4.732 kcal/mol, respectively. Further, MD Simulation was carried out and most of the interactions of molecular docking are preserved during simulation. The prominent interactions that our test ligands showed during MD Simulation are similar to drugs that possess in vitro anticovid activity as shown in recent studies. Hence, our test ligands possessed potential for anticovid activity and they should be further tested through in vitro and in vivo studies for their activity against COVID-19.Communicated by Ramaswamy H. Sarma.

Remdesivir-Associated Acute Liver Failure in a COVID-19 Patient: A Case Report and Literature Review.

There is a broad classification of the causes of acute liver failure (ALF) that include drug-induced liver injury (DILI). In this report, we aim to discuss the association between remdesivir, a novel therapeutic drug for hypoxic coronavirus disease 2019 (COVID-19) pneumonia, and DILI with subsequent ALF in a patient who was recently treated with the drug in question. Remdesivir, which is a direct-acting nucleoside RNA polymerase inhibitor, is one of the only FDA-approved drugs on the market for COVID-19 pneumonia associated with hypoxia. Our case describes a patient with an extensive past medical history who was treated for COVID-19 pneumonia with remdesivir and subsequently developed ALF in the absence of all other possible etiologies. This association has only been highlighted in anecdotal case reports in the past and to a lesser degree in the safety documentation of remdesivir.

Sevoflurane-Induced Diffuse Alveolar Hemorrhage.

Diffuse alveolar hemorrhage (DAH) is a potentially life-threatening pulmonary pathology which results in intra-alveolar hemorrhage secondary to disruption of the alveolar capillary basement membrane. Most commonly, these patients present with hemoptysis, hypoxemia and pulmonary infiltrates. Although rare, sevoflurane, an inhalational anesthetic used as a rapid induction agent for anesthesia may be implicated in the etiology of DAH. We report a case of a 21-year-old otherwise healthy male found to have postoperative diffuse alveolar hemorrhage secondary to sevoflurane inhalation. Thus far, only five documented cases describing sevoflurane induced diffuse alveolar hemorrhage have been described in the literature, with prior cases also showing a clear temporal association between sevoflurane administration and symptom onset. Although uncommon, we must take sevoflurane into consideration as a possible etiology of diffuse alveolar hemorrhage when encountering signs of respiratory distress and hemoptysis in postoperative patients.

Synchronous Liver Abscess With Cholecystitis: A Rare Case of Initial Presentation of Gallbladder Cancer Posing a Diagnosis Challenge.

Gallbladder carcinoma (GBC) is the most common of all biliary tract cancers. GBC is a multifactorial disease. Gallbladder dysplasia from any gallbladder inflammatory condition is one of the main risk factors for GBC. The late diagnosis of GBC is a major problem in its treatment. It is treated by radical resection and the prognosis is improved by adjuvant chemoradiation. We present a rare case of gall bladder cancer presenting as hepatic abscesses with severe sepsis. An 83-year-old male presented with progressive symptoms of shakiness, general weakness, vomiting, and profuse diarrhea. Lab work revealed deranged liver enzymes. Computed tomography (CT) and magnetic resonance cholangiopancreatography (MRCP) abdomen revealed intrahepatic abscesses contiguous with the gallbladder lumen through a gallbladder wall defect and cholecystitis of unknown chronicity. Subsequently, he underwent central hepatectomy and the pathology report of the sample as well as endoscopic retrograde cholangiopancreatography (ERCP) brushings revealed gallbladder adenocarcinoma. The case was complicated by biloma, acute renal failure, and the development of malignant ascites, and the patient died almost four months after the diagnosis of gallbladder cancer.

Postinfarction Ventricular Septal Ruptures During the COVID-19 Pandemic: Two Case Series.

This case series highlights the occurrence of hemodynamically significant ventricular septal defects (VSDs) in two patients presenting with ST-elevation myocardial infarction (STEMI) during the COVID-19 pandemic. This paper aims to emphasize the delayed presentation of cardiac emergencies, such as STEMI, due to concerns about contracting COVID-19. This delay has led to an increased risk of rare complications, including VSD, associated with STEMI. The first case involves a 92-year-old male with a history of hypertension, hyperlipidemia, chronic kidney disease, and coronary artery disease. He presented with acute chest pain, and diagnostic tests revealed ST elevations and a VSD. Despite intervention efforts, including hemodynamic support, the patient's condition deteriorated, and he passed away due to advanced age and high surgical risk. The second case involves a 62-year-old female with a medical history of diabetes, hypertension, and hyperlipidemia. She presented with left-sided chest pain, and an angiogram revealed a mid-right coronary artery stenosis and a thrombus. During the procedure, the patient experienced hypotension, requiring hemodynamic support. Subsequent evaluations identified a large VSD with right ventricular dysfunction. The patient underwent a series of interventions, including a ventricular assist device and VSD closure, but experienced multi-organ failure and ultimately passed away. VSDs following acute myocardial infarction (MI) are rare but life-threatening complications. Early revascularization is crucial in preventing the development of VSDs. These cases demonstrate the importance of prompt diagnosis and intervention, as delayed presentation increases the risk of mechanical complications. Surgical closure remains the definitive treatment for postinfarction VSDs.

Myocarditis as a Complication of Campylobacter jejuni-Associated Enterocolitis: A Report of Two Cases.

Myocarditis refers to inflammation of the heart muscle and may occur individually or together with pericarditis, which refers to inflammation of the saclike tissue layer that surrounds the heart. They may have infectious or non-infectious etiologies. Campylobacter jejuni, a major cause of gastroenteritis worldwide, may also cause myocarditis in rare situations. We present two cases highlighting this rare complication of diarrheal disease caused by Campylobacter jejuni infection and subsequent development of myocarditis. Both patients presented with chest pain and multiple episodes of watery diarrhea, with initial EKGs showing ST segment changes, as well as elevated inflammatory markers and elevated troponins. GI panels for both patients were positive for Campylobacter jejuni. Based on their presentations and investigative findings, they were diagnosed with myocarditis secondary to Campylobacter infection, and their symptoms subsided with appropriate management. It is unclear if the myocardial damage, in this case, is a direct effect of the toxin on cardiac myocytes or secondary to an immunologic phenomenon. Regardless, Campylobacter jejuni-associated myocarditis remains a rare phenomenon and needs to be considered in the differential of patients presenting with concurrent chest pain and diarrheal symptoms.

A Gut-Wrenching Feeling: Overcoming Cognitive Biases in an Atypical Presentation of Chronic Mesenteric Ischemia.

Chronic mesenteric ischemia is a rare but serious condition that can present with a variety of symptoms, including abdominal pain, diarrhea, and weight loss. Our case report presents a 63-year-old male with a past medical history of generalized anxiety disorder, Barrett's esophagus, hypertension, hyperlipidemia, chronic obstructive pulmonary disease (COPD) with active smoking who initially presented with severe diffuse abdominal pain, nausea, vomiting, and chronic diarrhea resulting in malnutrition and 40-pound weight loss over a six-month span. The patient underwent extensive diagnostic evaluation and was diagnosed with Yersinia gastroenteritis via gastroenteritis panel (GI Panel), explaining all of the patient's symptoms. The patient underwent treatment for said gastroenteritis but did not experience remission of symptoms, leading to further diagnostic evaluations; a definitive diagnosis was not found, yet the patient's symptoms persisted. The patient then underwent extensive serologic and endoscopic evaluation, after extensive imaging and diagnostic work-up, the patient was finally diagnosed with chronic mesenteric ischemia (CMI) of the superior mesenteric artery (SMA) with severe celiac and inferior mesenteric artery (IMA) stenosis. The patient initially underwent stenting (7 mm by 26 mm Balloon Mounted LifestreamTM Covered Stent; Becton Dickson (BD); Franklin Lakes, NJ, USA), which provided temporary relief to his symptoms, however, the relief did not last long. Upon reimaging, the patient was found to have stenosis of the stent, leading to the eventual placement of a bare-metal stent (ExpressTM LD 7 x 27 mm balloon mounted bare-metal stent; Boston Scientific; Boston, MA, USA) across the celiac artery as well as the placement of an IMA stent (InnovaTM Self-expanding 5 x 20 mm bare-metal stent; Boston Scientific). This eventually resulted in the resolution of the patient's symptoms, eventual weight gain, and improvement in quality of life.

Sickle Cell Anemia Associated With Increased In-Hospital Mortality in Post-Cardiac Arrest Patients.

Introduction Sickle cell anemia (SCA) is a hemoglobinopathy that arises from a point mutation in the beta-globin gene, which causes the polymerization of deoxygenated hemoglobin that leads to a wide variety of clinical complications. Deaths in patients with SCA most commonly arise from renal, cardiovascular disease, infections, and stroke. In-hospital cardiac arrest has been found to be more common in older patients and those on ventilatory life support, among others. This study aims to provide more insight into how SCA affects the risk of in-hospital mortality in post-cardiac arrest patients. Methods The National Inpatient Survey database years 2016 to 2019 was utilized. The International Classification of Diseases, Tenth Revision, Procedure Coding System (ICD-10 PCS) codes for cardiopulmonary resuscitation were used to identify in-hospital cardiac arrest (IHCA) patients. ICD-10 Clinical Modification (CM) codes were used to identify SCA and other medical comorbidities. Categorical data was compared using Person's chi-square test, and continuous variables were compared using the independent samples t-test. Multinomial logistic regression was used to study the effects of SCA on post-arrest in-hospital mortality controlling for age, Charlson comorbidity score, and demographic variables. Binomial logistic regression models for dichotomous variables were utilized in the subgroup and secondary outcomes analysis. Results In patients with IHCA, patients who had SCA were found to have a significantly increased risk of in-hospital mortality adjusted for baseline characteristics and Charlson comorbidity score (OR: 1.16, 95% CI: 1.02-1.32, p=0.0025). Patient characteristics most strongly associated with an increased risk of in-hospital mortality in this cohort were found to be Black race (OR: 1.92, 95% CI: 1.87-1.97, p<0.001) and self-payer status (OR: 2.14, 95% CI: 2.06-2.22, p<0.001). Subgroup analysis revealed only patients with sickle cell disease had a statistically significant increased risk of in-hospital mortality in this cohort (OR: 4.41, 95% CI: 3.5-5.55, p<0.001), and patients with sickle cell trait did not. Conclusion In patients with IHCA, SCA is associated with an increased risk of in-hospital mortality. This risk was confined to patients with sickle cell disease and not patients with sickle cell trait.

A review of treatment options employed in relapsed/refractory AML.

INTRODUCTION: Acute myeloid leukemia [AML] is a heterogenous group of primary hematopoietic neoplasms arising from myeloid precursor cells. Up to 50% of patients failed to achieve remission with initial therapy and go on to develop refractory AML. Whenever possible, enrollment in a clinical trial in view of the paucity of evidence surrounding a clearly superior treatment modality is recommended, and the therapy which provides the best chance for cure post remission is allogeneic hematopoietic stem cell transplantation [HCT], with much of everyday clinical decision-making in relapsed/refractory (R/R) AML surrounding the choice of the least toxic regimen that could achieve remission and enable prompt HCT. DISCUSSION: We discuss a variety of treatment modalities employed in the R/R AML setting beginning with traditional cytotoxic regimens. We then turn our attention to targeted therapies that have shown efficacy in specific patient populations such as the IDH inhibitors and FLT3 inhibitors and lastly, we turn our attention to immunotherapeutic agents employed in the R/R in the setting, such as CD33 inhibitors and bispecific antibodies. CONCLUSION: It appears increasingly clear that approaching AML as a homogenous disease entity is unsatisfactory in view of the variations in such disease factors as cytogenetic and molecular markers, age, and disease severity at presentation; all of which contribute significantly to heterogeneity of the disease. Moving forward, treating AML would likely require tailored therapy following advances in technology such as molecular profiling, drug sensitivity and resistance testing.

Evaluating Dental Fear and Anxiety in Pediatric Patients Visiting a Private and a Public Dental Hospital in Lahore, Pakistan.

Background One of the biggest hurdles in treating pediatric patients is managing dental fear and anxiety. Some factors that contribute to an increase in dental anxiety are fear of pain, the presence of unknown individuals, a change in the setting of an environment, and separation from parents. Aim The aim of this study was to evaluate dental fear and anxiety in pediatric patients, between the ages of 6 and 12 years, visiting private and public dental hospitals using the Children's Fear Survey Schedule-Dental Subscale (CFSS-DS). Methods A total of 280 children, 140 in a private dental hospital setting and 140 in a public dental hospital setting, were enrolled in this study. The purpose of the study was explained to the accompanying guardian of the patient and written consent was taken. The CFSS-DS was explained verbally in Urdu and the questionnaire was given to guardians alongside the patients which they were asked to fill out following their dental treatment. Result The data obtained from the questionnaires were analyzed using the unpaired t-test. The highest dental fear mean scores and standard deviation in a private dental hospital were for "choking" (3.25 ± 1.21), "the noise of the dentist drilling" (3.24 ± 1.04), and "having somebody put instruments in your mouth" (3.19 ± 1.06), whereas, for a public dental hospital, the highest fear score was recorded in "choking" (3.17 ± 1.69), "injections" (3.07 ± 1.72), and "people in white uniforms" (1.90 ± 1.21). Conclusion The study showed a higher prevalence of dental fear and anxiety in a private dental setting when compared to a public dental setting. Factors responsible for an increase in dental fear need to be assessed for each patient and then treatment given accordingly.

A Rare Initial Presentation of Aortic Intramural Hematoma: A Case Report and Literature Review.

Aortic intramural hematoma (AIH) is a life-threatening emergency that involves aortic wall integrity and is characterized by either a direct rupture of the vasa vasorum or spontaneous bleeding of an arterial plaque located in the tunica media of the aortic wall. A notable difference between AIH and acute aortic dissection is the absence of an intimal flap, a finding discernable on computed tomography angiography (CTA). Follow-up imaging allows for the monitoring of disease progression or early findings of impending complications. While some patients may require surgical intervention, medical management with blood pressure control remains the mainstay in treatment. Our case describes a patient who was found to be in cardiac arrest secondary to ventricular fibrillation and was then found to have presumed Stanford Type A aortic dissection on CTA. After reviewing the scans, the diagnosis was reclassified to AIH due to the absence of an intimal flap, the patient was then managed medically for AIH with antihypertensive medications.

Diagnostic dilemma in a patient presenting with thrombotic microangiopathy in the setting of pregnancy.

We report a case of thrombotic microangiopathy in a postpartum female for which considerable diagnostic uncertainty existed initially regarding the etiology. This case highlights the limitations surrounding PLASMIC scoring criteria for the diagnosis of thrombotic thrombocytopenic purpura (TTP). A 32-year-old woman presented to maternofetal medicine in her third trimester of pregnancy at 32 weeks for a routine follow up and was subsequently found to have elevated blood pressures with proteinuria, and was diagnosed with pre-eclampsia. Worsening anemia and thrombocytopenia prompted a blood smear which showed schistocytes, concerning for a thrombotic microangiopathy. Creatinine was also elevated with normal liver enzymes being noted. A PLASMIC score of 4 placed her in the low-risk category for severe ADAMTS13 deficiency whilst she fulfilled criteria for partial HELLP (hemolysis, elevated liver enzymes and low platelets) syndrome per Tennessee classification. Despite delivery, her symptoms persisted with subsequent ADAMTS13 assay confirming acquired TTP, subsequently requiring repeated plasmapheresis and rituximab to achieve disease control. Thrombotic microangiopathy remains a diagnostic challenge especially in the peripartum population, and scoring systems such as PLASMIC score and Tennessee classification may be of limited utility.

A Case of Plasmablastic Multiple Myeloma With Extramedullary Disease Manifesting as a Myelomatous Pleural Effusion.

Multiple myeloma (MM) is a neoplasm of plasma cell origin characterized by the proliferation of immunoglobulin-producing plasma cells in the bone marrow. Extramedullary disease (EMD) occurs in approximately 10% of patients with MM. Myelomatous pleural effusion (MPE) is a possible manifestation of EMD and has been associated with a poorer prognosis. A 66-year-old female was evaluated after an abnormal serum protein electrophoresis that showed a 2.1 g/dL M-spike in the gamma region, highly suggestive of plasma cell dyscrasia. Imaging subsequently confirmed the bony metastasis. A bone marrow biopsy confirmed plasmablastic MM, and she was started on chemotherapy. She presented three months later with bilateral pleural effusions, with cytology revealing neoplastic plasmacytoid cells. Despite transitioning to dexamethasone, cyclophosphamide, etoposide, and cisplatin (the V-DCEP regimen) due to disease progression, her myeloma remained refractory to treatment, and she expired one month later. MPE in MM is associated with a poor prognosis, with a median overall survival (OS) of 13 months in MPE compared to 37 months in other EMDs. A higher tumor burden and greater multisite extra-medullary lesions are also characteristics of MPE in MM. There is no standard of care for the management of EMD, and salvage regimens such as RVD and V-DCEP are commonly employed. The management of MM with EMD remains a challenge, and more investigation is required before effective treatment regimens may be employed in this setting.

A Rare Case of Pseudomembrane-Associated Ulcerative Colitis.

Ulcerative colitis (UC) is a chronic, life-long inflammatory bowel disease that normally presents with bloody diarrhea, fever, abdominal pain, and leukocytosis. Diagnosis is usually based on clinical presentation, endoscopy with biopsy, and exclusion of alternative diagnoses. In very rare cases, pseudomembranes may be found on colonoscopy in patients with an early UC flare. Historically, the objective finding of pseudomembranes has been exclusively used to diagnose a Clostridioides difficile infection (CDI); however, diagnostic testing must be correctly utilized to confirm whether a CDI is truly the cause of the presence of pseudomembranes, and not an alternative etiology, such as UC. In this case, we discuss a 43-year-old female who presented to the hospital with worsening chronic bloody diarrhea after being seen in the outpatient clinic for a questionable CDI. She underwent endoscopic evaluation revealing pseudomembranous colitis; however, C. difficile testing showed one positive gastrointestinal (GI) pathogen panel and multiple negative antigens and toxin enzyme immunoassays (EIA). With a clinical suspicion of early UC, the patient was treated with mesalamine enemas and improved clinically before discharge. Several months later, she underwent endoscopic evaluation with biopsy, which showed findings consistent with a diagnosis of UC.

Gut-brain axis: Review on the association between Parkinson's disease and plant lectins.

Gastrointestinal (GI) involvement in the pathogenesis of Parkinson's Disease (PD) has been widely recognized and supported in recent literature. Prospective and retrospective studies found non-motor symptoms within the GI, specifically constipation, precede cardinal signs and cognitive decline by almost 20 years. In 2002, Braak et al. were the first to propose that PD is a six-stage propagating neuropathological process originating from the GI tract (GIT). Aggregated α-synuclein (α-syn) protein from the GIT is pathognomonic for the development of PD. This article reviews the current literature from the past 10 years as well as original research found in PubMed on the combined effects of enteric glial cells and lectins on the development of Parkinson's Disease. Studies have found that these aggregated and phosphorylated proteins gain access to the brain via retrograde transport through fast and slow fibers of intestinal neurons. Plant lectins, commonly found within plant-based diets, have been found to induce Leaky Gut Syndrome and can activate enteric glial cells, causing the release of pro-inflammatory cytokines. Oxidative stress on the enteric neurons, caused by a chronic neuro-inflammatory state, can cause a-syn aggregation and lead to Lewy Body formation, a hallmark finding in PD. Although the current literature provides a connection between the consumption of plant lectins and the pathophysiology of PD, further research is required to evaluate confounding variables such as food antigen mimicry and other harmful substances found in our diets.