Unveiling the Ro60-Ro52 complex.

The coexistence within a subcellular complex of inter-cellular proteins Ro60, responsible for preserving ncRNA quality, and Ro52, involved in intracellular proteolysis, has been a subject of ongoing debate. Employing molecular docking in tandem with experimental methods like Quartz Crystal Microbalance with Dissipation (QCM-D), Proximity Ligation Assay (PLA), and Indirect Immunofluorescence (IIF), we reveal the presence of Ro60 associating with Ro52 within the cytoplasm. This result unveils the formation of a weak transient complex with a Ka ≈ (3.7 ± 0.3) x 106 M-1, where the toroid-shaped Ro60 structure interacts with the Ro52's Fc receptor, aligning horizontally within the PRY-SPRY domains of the Ro52's homodimer. The stability of this complex relies on the interaction between Ro52 chain A and specific Ro60 residues, such as K133, W177, or L185, vital in the Ro60-YRNA bond. These findings bridge the role of Ro60 in YRNA management with Ro52's function in intracellular proteolysis, emphasizing the potential impact of transient complexes on cellular pathways. See also the graphical abstract(Fig. 1).

Adolescents' use of online food delivery applications and perceptions of healthy food options and food safety: a cross-sectional study in the United Arab Emirates.

Introduction: This cross-sectional study aimed to assess Online food delivery applications (OFDA) usage trends among adolescent users in the United Arab Emirates (UAE), focusing on their perceptions of healthy food options and food safety (n = 532). Methods: Sociodemographic information, frequency of OFDA use, factors affecting food choices, and perceptions of healthy food and food safety were investigated. A total perception score was calculated for each participant. Results: Most participants used OFDAs weekly (65.4%), favoring fast food (85.7%). Factors like appearance and price drove food choices (65.0%), while taste and cost hindered healthy food orders (29.7 and 28.2%). Younger and frequent users had lower scores for perceiving healthy food, while seeking healthy options was associated with higher scores (p < 0.05). Females and those seeking healthy food showed higher food safety scores (p < 0.05). Discussion: The study suggests tailored interventions to promote healthier choices and improve food safety perceptions among adolescents using OFDAs in the UAE.

Antibiotic Augmentation of Thermal Eradication of Staphylococcus epidermidis Biofilm Infections.

Staphylococcus epidermidis is a major contributor to bacterial infections on medical implants, currently treated by surgical removal of the device and the surrounding infected tissue at considerable morbidity and expense. In situ hyperthermia is being investigated as a non-invasive means of mitigating these bacterial biofilm infections, but minimizing damage to the surrounding tissue requires augmenting the thermal shock with other approaches such as antibiotics and discerning the minimum shock required to eliminate the biofilm. S. epidermidis biofilms were systematically shocked at a variety of temperatures (50-80 °C) and durations (1-10 min) to characterize their thermal susceptibility and compare it to other common nosocomial pathogens such as Staphylococcus aureus and Pseudomonas aeruginosa. Biofilms were also exposed to three classes of antibiotics (ciprofloxacin, tobramycin and erythromycin) separately at concentrations ranging from 0 to 128 µg mL-1 to evaluate their impact on the efficacy of thermal shock and the subsequent potential regrowth of the biofilm. S. epidermidis biofilms were shown to be more thermally susceptible to hyperthermia than other common bacterial pathogens. All three antibiotics substantially decreased the duration and/or temperature needed to eliminate the biofilms, though this augmentation did not meet the criteria of synergism immediately following thermal shock. Subsequent reincubation, however, revealed strong synergism on a longer timescale.

Exercise Prevents Glucocorticoid-Induced Myocardial 4-Hydroxynonenal Production.

PURPOSE: Long-term administration of glucocorticoids (GCs) increases myocardial oxidative stress. 4-Hydroxynonenal (4-HNE) protein adducts, a marker of oxidative damage, have been associated with several cardiovascular diseases, including atherosclerosis, cardiac hypertrophy, cardiomyopathy, and ischemia-reperfusion injury. Exercise training has been shown to have a protective effect on the heart by lowering the level of oxidative stress in cardiomyocytes. Therefore, we aimed to investigate the effect of long-term dexamethasone treatment and exercise training on myocardial 4-HNE levels. METHODS: Twenty-four female Wistar albino rats were assigned to sedentary control-saline treated (C, n = 8), sedentary-dexamethasone treated (D, n = 8), and exercise training-dexamethasone treated (DE, n = 8) groups. Daily dexamethasone was injected for 28 days at a 1 mg kg-1 dose, while C animals were injected with the same volume of saline subcutaneously. DE animals underwent an exercise training protocol of 60 min/day, 5 days a week, at 25 m/min-1 (0% grade) for 28 days. Left ventricular 4-HNE, Hsp72 levels, and pHsp25/Hsp25 ratio were determined by Western blot. RESULTS: The administration of dexamethasone led to a significant elevation in 4-HNE levels in the myocardium of adult rats (p < 0.05; D vs. C). The concurrent implementation of exercise training impeded this increase (p > 0.05; DE vs. C). Exercise training induced a threefold increase in myocardial Hsp72 expression (p < 0.001; DE vs. C and D) and attenuated the dexamethasone-induced increase in Hsp25 phosphorylation (p < 0.05; C vs. D) (p < 0.001; DE vs. D). CONCLUSION: Our results indicate that long-term administration of dexamethasone is associated with an increase in cardiac 4-HNE levels, which is hindered by the addition of exercise training.

Thermal susceptibility and antibiotic synergism of methicillin-resistant Staphylococcus aureus biofilms.

Methicillin-Resistant Staphylococcus aureus (MRSA) biofilms are among the most dangerous infections on medical implants, typically requiring surgical explantation and replacement. This study investigated the thermal susceptibility of MRSA biofilms to thermal shocks from 60 to 80 °C for 1-30 min as well as the effect of various antibiotics (most notably methicillin) on thermal mitigation. Pre- and post-shock exposure to three different classes of antibiotics (ciprofloxacin, tobramycin, and methicillin) at concentrations ranging from 0.25 to 128 µg mL-1 were investigated. MRSA biofilms exhibited thermal susceptibility comparable to other common nosocomial pathogens, such as Pseudomonas aeruginosa, though with greater variability. Exposure to antibiotics of any class significantly decreased the degree of thermal shock required for reliable mitigation, including at subclinical concentration. These combined treatments reduced biofilm population more than the sum of thermal and chemical treatments alone, demonstrating synergism, while also indicating a critical population drop of ∼4.5 log10 beyond which the biofilms typically became non-viable.

Unveiling the Stereoselectivity and Regioselectivity of the [3+2] Cycloaddition Reaction between N-methyl-C-4-methylphenyl-nitrone and 2-Propynamide from a MEDT Perspective.

[3+2] cycloaddition reactions play a crucial role in synthesizing complex organic molecules and have significant applications in drug discovery and materials science. In this study, the [3+2] cycloaddition (32CA) reactions of N-methyl-C-4-methyl phenyl-nitrone 1 and 2-propynamide 2, which have not been extensively studied before, were investigated using molecular electron density theory (MEDT) at the B3LYP/6-311++G(d,p) level of theory. According to an electron localization function (ELF) study, N-methyl-C-4-methyl phenyl-nitrone 1 is a zwitterionic species with no pseudoradical or carbenoid centers. Conceptual density functional theory (CDFT) indices were used to predict the global electronic flux from the strong nucleophilic N-methyl-C-4-methyl phenylnitrone 1 to the electrophilic 2-propynamide 2 functions. The 32CA reactions proceeded through two pairs of stereo- and regioisomeric reaction pathways to generate four different products: 3, 4, 5, and 6. The reaction pathways were irreversible owing to their exothermic characters: -136.48, -130.08, -130.99, and -140.81 kJ mol-1, respectively. The enthalpy of the 32CA reaction leading to the formation of cycloadduct 6 was lower compared with the other path owing to a slight increase in its polar character, observed through the global electron density transfer (GEDT) during the transition states and along the reaction path. A bonding evolution theory (BET) analysis showed that these 32CA reactions proceed through the coupling of pseudoradical centers, and the formation of new C-C and C-O covalent bonds did not begin in the transition states.

Long-term Dexamethasone Treatment Increases Cardiac Galectin-3 Levels.

PURPOSE: Glucocorticoids, which are widely prescribed around the world, cause cardiac remodeling in long-term treatment by triggering insulin resistance and increasing blood pressure. However, its role in cardiac remodeling remains unclear. Galectin-3 (gal-3) is a member of a beta-galactoside-binding animal lectins, upregulated as a result of insulin resistance and in the pressure-overloaded myocardium and regulate cardiac remodeling. We hypothesized that gal-3 may be upregulated in the myocardium with prolonged use of glucocorticoids and associated with cardiac hypertrophy. METHODS: To examine the involvement of glucocorticoids in gal-3 levels in rat myocardium, sixteen female Wistar Albino rats were assigned to control (C; n = 8) and dexamethasone (Dex; n = 8) groups. Daily dexamethasone was injected subcutaneously for 28 days at a dose of 1 mg.kg-1. Control animals were injected with the same volume of saline. The body weight and heart weights were determined. Gal-3 levels in myocardium were determined by Western blot. RESULTS: Our data shows that dexamethasone administration resulted in significant increase in heart weight (p < 0.05) and HW/BW ratios (p < 0.001) and 28 days of dexamethasone administration with the dose of 1 mg.kg-1 caused a twofold increase in the gal-3 expression in the left ventricle (p < 0.001). CONCLUSION: The finding of the current study is the first to show that dexamethasone causes an increase in gal-3 levels in myocardium. Our study provides an important step in the development of possible therapeutics by determining that dexamethasone causes an increase in gal-3 levels in the myocardium and raises awareness about the follow-up of patients receiving long-term glucocorticoid therapy.

Lifting the Mouth Corner: A Systematic Review of Techniques, Clinical Outcomes, and Patient Satisfaction.

BACKGROUND: Mouth corners are an essential part of the centrofacial area for perception of attractiveness and emotions. Downturned mouth corners are a result of aging or have a congenital origin. Different mouth corner lifting techniques are described in the literature. OBJECTIVES: This review was performed to systematically assess and compare invasive and noninvasive mouth corner lifting techniques and their effectiveness, patient satisfaction, and adverse effects. METHODS: MEDLINE (via PubMed), EMBASE (OvidSP), and the Cochrane Central Register of controlled trials databases were searched for clinical and observational studies published in peer-reviewed academic journals with abstracts available (searched from May 18, 2019, to December 18, 2021). Outcomes of interest were aesthetic mouth corner lifting techniques, the degree of lift as well as the longevity of the lifting effect, patient satisfaction, and adverse effects. Techniques were subdivided in invasive techniques and noninvasive techniques. RESULTS: Out of 968 studies found from the search, 11 were included in the qualitative analysis. In general, surgical techniques seem to have a better mouth corner lifting effect than nonsurgical techniques; however, objective evidence is weak, and surgery inevitably results in a scar. Reported patient satisfaction was good for both surgical and nonsurgical techniques and no severe complications have been described. CONCLUSIONS: Surgical techniques seem to have a better lifting effect on mouth corners than nonsurgical techniques. Nevertheless, objective evidence is weak, and a scar is inevitable.

Gastric outlet obstruction - looking for a syndrome: Bouveret or Mirizzi?

INTRODUCTION AND IMPORTANCE: Gastric outlet obstruction can result from any pathological process that causes intrinsic blockage or extrinsic pressure on the distal stomach and duodenum. Gallstone related gastric outlet obstruction is a well-known entity classically due to a cholecystoenteric fistula formation. CASE PRESENTATION: We present here a case of a 36-year-old man who presented with right upper quadrant abdominal pain associated with marked nausea and vomiting. Abdominal CT scan done in the emergency department revealed a large impacted infundibular gallstone with signs of acute cholecystitis, associated with prominent gastric distention. Gastric outlet obstruction was due to stenosis at the duodenal level from external compression by the large impacted stone with no evidence of fistula. Laparoscopic cholecystectomy was performed with total resolution of symptoms. CLINICAL DISCUSSION: Gastric outlet obstruction can be secondary to many etiologies, and notably gallstone disease. Classically this is due to formation of a cholecystoenteric fistula and intrinsic obstruction by the migrated stone. Our case is unique in that a large impacted infundibular gallstone caused gastric outlet obstruction with absence of any fistula or gallstone migration. CONCLUSION: Gastric outlet obstruction due to external compression by a non-migrated gallstone is a rare undescribed entity. Surgical treatment should not be delayed to prevent complications and fistula formation.

Safety, Tolerability, and Population Pharmacokinetics of Intravenous and Oral Isavuconazonium Sulfate in Pediatric Patients.

Isavuconazole, administered as the water-soluble prodrug isavuconazonium sulfate, is a new triazole agent used to treat invasive fungal infections. This phase 1 study evaluated the pharmacokinetics (PK), safety, and tolerability of isavuconazole in 46 immunocompromised pediatric patients, stratified by age (1 to <6 [intravenous (i.v.) only], 6 to <12, and 12 to <18 years), receiving 10 mg/kg body weight (maximum, 372 mg) isavuconazonium sulfate either i.v. or orally. A population PK model using weight-based allometric scaling was constructed with the pediatric i.v. and oral data plus i.v. data from a phase 1 study in adults. The best model was a 3-compartment model with combined zero-order and first-order input, with linear elimination. Stepwise covariate modeling was performed in Perl-speaks-NONMEM version 4.7.0. None of the covariates examined, including age, sex, race, and body mass index, were statistically significant for any of the PK parameters. The area under the concentration-time curve at steady state (AUCSS) was predicted for pediatric patients using 1,000 Monte Carlo simulations per age cohort for each administration route. The probability of target attainment (AUCSS range, 60 to 233 µg · h/ml) was estimated; this target range was derived from plasma drug exposures in adults receiving the recommended clinical dose. Predicted plasma drug exposures were within the target range for >80% and >76% of simulated pediatric patients following i.v. or oral administration, respectively. Intravenous and oral administration of isavuconazonium sulfate at the studied dosage of 10 mg/kg was well tolerated and resulted in exposure in pediatric patients similar to that in adults. (This study has been registered at ClinicalTrials.gov under identifier NCT03241550).

Impact of depth of clinical response on outcomes of acute myeloid leukemia patients in first complete remission who undergo allogeneic hematopoietic cell transplantation.

Acute myeloid leukemia (AML) patients often undergo allogeneic hematopoietic cell transplantation (alloHCT) in first complete remission (CR). We examined the effect of depth of clinical response, including incomplete count recovery (CRi) and/or measurable residual disease (MRD), in patients from the Center for International Blood and Marrow Transplantation Research (CIBMTR) registry. We identified 2492 adult patients (1799 CR and 693 CRi) who underwent alloHCT between January 1, 2007 and December 31, 2015. The primary outcome was overall survival (OS). Multivariable analysis was performed to adjust for patient-, disease-, and transplant-related factors. Baseline characteristics were similar. Patients in CRi compared to those in CR had an increased likelihood of death (HR: 1.27; 95% confidence interval: 1.13-1.43). Compared to CR, CRi was significantly associated with increased non-relapse mortality (NRM), shorter disease-free survival (DFS), and a trend toward increased relapse. Detectable MRD was associated with shorter OS, shorter DFS, higher NRM, and increased relapse compared to absence of MRD. The deleterious effects of CRi and MRD were independent. In this large CIBMTR cohort, survival outcomes differ among AML patients based on depth of CR and presence of MRD at the time of alloHCT. Further studies should focus on optimizing post-alloHCT outcomes for patients with responses less than CR.

Possible value of galectin-3 on follow-up of cardiac remodeling during glucocorticoid treatment.

Glucocorticoids are among the most prescribed drugs globally due to their potent anti-inflammatory and immunosuppressive properties. Although they have positive effects on the treatment of various disease states; long-term administration is associated with high blood pressure, insulin resistance, and susceptibility to type 2 diabetes. The heart attempts to cope with increased blood pressure and a decrease in glucose utilization by developing pathological cardiac remodeling. However, in this process, cardiac fibrosis formation and deterioration in heart structure and functions occur. Galectin-3, a member of the ß-galactoside binding lectins, is consistently associated with inflammation and fibrosis in the pathogenesis of various disease states including insulin resistance and heart failure. Galectin-3 expression is markedly increased in activated macrophages and a subset of activated fibroblasts and vascular cells. Also, failing and remodeling myocardium show increased Gal-3 expression and elevated Gal-3 levels are related to heart failure severity and prognosis. Furthermore, Gal-3-related pathways are recently suggested as therapeutic targets both pharmacologically and genetically to increase insulin sensitivity in vivo. The objective of this review is to provide a summary of our current understanding of the role of glucocorticoid-associated insulin resistance, which is important for some cardiac events, and the potential role of galectin in this pathophysiological process.

Laparoscopic Gastric Bypass Reversal with Concomitant Sleeve Gastrectomy (SG) for Refractory Hypoglycemia: an Unusual Procedure.

INTRODUCTION: Post-bariatric surgery hypoglycemia is usually seen in patients with a history of gastric bypass surgery [1], and few experience severe symptoms [2]. The pathophysiology of post-gastric bypass surgery hypoglycemia is not well understood, and many theories have been proposed: excessive GLP-1, nesidioblastosis, and increased glucose effectiveness [3]. Thus, the etiology of this condition is complex. Laparoscopic GBP reversal is a very unusual procedure and indications may include excessive weight loss, unexplained GI tract symptoms, and severe hypoglycemia. Hypoglycemia should be managed non-surgically at first, but in case of medical therapy failure, surgical options may be considered. Surgical options include gastrostomy tube placement, gastric bypass reversal [4], or gastric bypass reversal with concomitant sleeve gastrectomy [5-7]. A partial reversal was also mentioned in the literature [6]. Laparoscopic conversion to a sleeve gastrectomy for hypoglycemia is unusual and converting an open gastric bypass to a laparoscopic sleeve gastrectomy is exceptional, even never reported. In this video (run time 6 min and 48 s), we present our procedure, which was performed by adopting a new technique. PATIENT AND METHODS: A 52-year-old lady was referred to us for hypoglycemia following an open gastric bypass revision that was done in 2012. Her past surgical history includes 2 laparoscopic gastric band surgeries with subsequent removal of the bands, open bypass surgery in 2007 and open bypass surgery revision in 2012. History goes back to 12 months ago when the patient started complaining of fatigue, lassitude, and symptoms consistent with Whipple's triad. OGTT (oral glucose tolerance test) showed low glucose levels at 2 h (2.7 mmol/l) and at 3 h (3.3 mmol/l). Serum insulin level and C-peptide were normal. The patient was diagnosed as having early dumping syndrome (reactive hypoglycemia). She was started on sitagliptin 1 tab once daily with dietary changes. Despite this management, she was hospitalized several times for worsening of her symptoms. When referred to our department, the patient asked about the possibility of a laparoscopic intervention, since she has suffered a lot from her previous laparotomy incisions. The laparoscopic surgery intervention was discussed with the patient and it was a challenging option in this case. The patient was placed in the lithotomy position with the surgeon standing between the patient's legs. An 11-mm trocar was inserted above the umbilicus. Under vision, 4 other trocars were inserted: a 12-mm trocar in the right midclavicular line and three 5-mm trocars in the epigastrium, left anterior axillary line, and left midclavicular line, respectively. We started with adhesiolysis in order to identify the gastro-jejunostomy and to free the abdominal esophagus. A subtle hiatal hernia was also reduced. Then, the jejuno-jejunostomy was identified, and the alimentary limb was measured. The latter was 70 cm in length, and the decision was to resect it, keeping the jejuno-jejunal anastomosis in place. The gastric pouch was divided just above the gastro-jejunal anastomosis. The alimentary limb was then exteriorized. Then, the gastric remnant was freed from its omental attachment. The gastric remnant and the gastric pouch were calibrated with a 40-Fr Faucher tube, and appropriate sequential firing was done using endo-GIA. A gastro-gastrostomy was fashioned by the end of the sleeve division to create the gastric tube. RESULTS: The operative time was 245 min, with minor blood loss (less than 250 cc). The perioperative course was uneventful, with no intra-operative or post-operative morbidity. An upper GI series was done on post-operative day 2 and showed no evidence of leak. It has been 11 months since the procedure and the patient has become normoglycemic. Her last FBS was 4.4 mmol and she is currently free of symptoms. DISCUSSION AND CONCLUSION: Post-bariatric surgery hypoglycemia is a challenging condition, for both surgeons and endocrinologists. Our patient has suffered severe symptoms that were refractory to medical treatment and dietary modifications. Few papers have discussed LGBP conversion to a sleeve gastrectomy for hypoglycemia, but results from small series are showing promising results. Our case was challenging because of the patient's previous multiple open surgeries and the technique we have adopted is unique, since we have fashioned the sleeve by firing 2 separate gastric pouches (gastric pouch and gastric remnant) to create a gastric tube and by performing a gastro-gastrostomy with intra-corporeal sutures.

Neighborhood poverty and pediatric allogeneic hematopoietic cell transplantation outcomes: a CIBMTR analysis.

Social determinants of health, including poverty, contribute significantly to health outcomes in the United States; however, their impact on pediatric hematopoietic cell transplantation (HCT) outcomes is poorly understood. We aimed to identify the association between neighborhood poverty and HCT outcomes for pediatric allogeneic HCT recipients in the Center for International Blood and Marrow Transplant Research database. We assembled 2 pediatric cohorts undergoing first allogeneic HCT from 2006 to 2015 at age ≤18 years, including 2053 children with malignant disease and 1696 children with nonmalignant disease. Neighborhood poverty exposure was defined a priori per the US Census definition as living in a high-poverty ZIP code (≥20% of persons below 100% federal poverty level) and used as the primary predictor in all analyses. Our primary outcome was overall survival (OS), defined as the time from HCT until death resulting from any cause. Secondary outcomes included relapse and transplantation-related mortality (TRM) in malignant disease, acute and chronic graft-versus-host disease, and infection in the first 100 days post-HCT. Among children undergoing transplantation for nonmalignant disease, neighborhood poverty was not associated with any HCT outcome. Among children undergoing transplantation for malignant disease, neighborhood poverty conferred an increased risk of TRM but was not associated with inferior OS or any other transplantation outcome. Among children with malignant disease, a key secondary finding was that children with Medicaid insurance experienced inferior OS and increased TRM compared with those with private insurance. These data suggest opportunities for future investigation of the effects of household-level poverty exposure on HCT outcomes in pediatric malignant disease to inform care delivery interventions.

Infantile Myelofibrosis and Myeloproliferation with CDC42 Dysfunction.

Studies of genetic blood disorders have advanced our understanding of the intrinsic regulation of hematopoiesis. However, such genetic studies have only yielded limited insights into how interactions between hematopoietic cells and their microenvironment are regulated. Here, we describe two affected siblings with infantile myelofibrosis and myeloproliferation that share a common de novo mutation in the Rho GTPase CDC42 (Chr1:22417990:C>T, p.R186C) due to paternal germline mosaicism. Functional studies using human cells and flies demonstrate that this CDC42 mutant has altered activity and thereby disrupts interactions between hematopoietic progenitors and key tissue microenvironmental factors. These findings suggest that further investigation of this and other related disorders may provide insights into how hematopoietic cell-microenvironment interactions play a role in human health and can be disrupted in disease. In addition, we suggest that deregulation of CDC42 may underlie more common blood disorders, such as primary myelofibrosis.