The potency of mesenchymal stem/stromal cells: does donor sex matter?

Mesenchymal stem/stromal cells (MSCs) are a promising therapeutic tool in cell therapy and tissue engineering because of their multi-lineage differentiation capacity, immunomodulatory effects, and tissue protective potential. To achieve optimal results as a therapeutic tool, factors affecting MSC potency, including but not limited to cell source, donor age, and cell batch, have been investigated. Although the sex of the donor has been attributed as a potential factor that can influence MSC potency and efficacy, the impact of donor sex on MSC characteristics has not been carefully investigated. In this review, we summarize published studies demonstrating donor-sex-related MSC heterogeneity and emphasize the importance of disclosing donor sex as a key factor affecting MSC potency in cell therapy.

Evaluation of serum level of C-reactive protein (CRP) and its correlation with fetal ultrasound parameters in the prediction of threatened miscarriage in the first trimester.

BACKGROUND: Pregnancy loss occurring before 20 weeks gestation is referred to as miscarriage. Various clinical presentations of miscarriage include threatened, inevitable, incomplete, complete, septic, and missed miscarriage. Early-stage threatened miscarriage may manifest with symptoms such as abdominal discomfort and vaginal bleeding. Threatened miscarriage is clinically defined as the manifestation of positive fetal heart sounds in pregnancies occurring before the 20th week of gestation, concomitant with vaginal bleeding and a closed cervix. OBJECTIVES: The primary aim of this study was to evaluate the association between serum C-reactive protein (CRP) levels and fetal ultrasound findings in the prediction of threatened miscarriage during the first trimester of pregnancy. METHODS: In this prospective case-control study, a total of 100 pregnant women at 7-13 weeks of gestation were enrolled. All participants initially presented with a singleton embryo displaying cardiac activity on ultrasound. The study cohort was divided into two groups: Group 1 consisted of 50 women with uncomplicated pregnancies, while Group 2 comprised 50 women experiencing symptoms indicative of threatened miscarriage. RESULTS: Notably, within Group 2, patients who eventually experienced miscarriage exhibited significantly elevated serum high-sensitivity CRP levels in comparison to those who maintained their pregnancies. CONCLUSIONS: Threatened miscarriage cases demonstrated a substantial increase in serum high-sensitivity CRP levels compared to the control group. Furthermore, CRP levels exhibited a correlation with the risk of miscarriage, suggesting their potential utility in conjunction with ultrasound parameters for prognosticating threatened miscarriage during the first trimester.

THE ACCURACY OF INFERIOR VENA CAVA DISTENSIBILITY THROUGH THE TRANSHEPATIC APPROACH TO PREDICT FLUID RESPONSIVENESS IN PATIENTS WITH SEPTIC SHOCK AFTER EMERGENCY LAPAROTOMY.

ABSTRACT: Background: We aimed to evaluate the ability of inferior vena cava (IVC) distensibility using the transhepatic approach to predict fluid responsiveness in mechanically ventilated patients with septic shock after emergency laparotomy. Methods: This prospective observational study included mechanically ventilated paralyzed adult who had septic shock after emergency laparotomy. The IVC dimensions were measured through the transhepatic and subxiphoid approaches. The fluid responsiveness was confirmed with >15% increase in cardiac output after 500 mL of fluid bolus. The outcomes were the ability of transhepatic (primary outcome) and subxiphoid approach to predict fluid responders using the area under the receiver operating characteristics curve analysis. The gray zone for the two approaches was calculated. Results: Data from 51 patients were analyzed, and the number of fluid responders was 30 of 52 (58%). The transhepatic approach was feasible in all patients, whereas the subxiphoid approach was only feasible in 42 patients. The area under the receiver operating characteristics curve (95% confidence interval) for the transhepatic IVC distensibility was 0.88 (0.76-0.95), and it was comparable with that of the subxiphoid approach (0.81 [0.66-0.92], P = 0.417). The gray zone for the transhepatic IVC distensibility was 17% to 35% including 24 of 51 patients (47%), whereas the gray zone for the subxiphoid IVC distensibility was 13% to 34% including 18 of 42 patients (43%). Conclusion: In conclusion, the transhepatic approach for evaluation of IVC distensibility showed good accuracy in predicting fluid responsiveness in patients with septic shock after emergency laparotomy. The transhepatic approach showed the same accuracy as the subxiphoid approach with the advantage of being feasible in larger number of patients.

Mesenchymal stromal/stem cell (MSC)-derived exosomes in clinical trials.

Mesenchymal stromal/stem cells (MSCs) are widely utilized in cell therapy because of their robust immunomodulatory and regenerative properties. Their paracrine activity is one of the most important features that contribute to their efficacy. Recently, it has been demonstrated that the production of various factors via extracellular vesicles, especially exosomes, governs the principal efficacy of MSCs after infusion in experimental models. Compared to MSCs themselves, MSC-derived exosomes (MSC-Exos) have provided significant advantages by efficiently decreasing unfavorable adverse effects, such as infusion-related toxicities. MSC-Exos is becoming a promising cell-free therapeutic tool and an increasing number of clinical studies started to assess the therapeutic effect of MSC-Exos in different diseases. In this review, we summarized the ongoing and completed clinical studies using MSC-Exos for immunomodulation, regenerative medicine, gene delivery, and beyond. Additionally, we summarized MSC-Exos production methods utilized in these studies with an emphasis on MSCs source, MSC-Exos isolation methods, characterization, dosage, and route of administration. Lastly, we discussed the current challenges and future directions of exosome utilization in different clinical studies as a novel therapeutic strategy.

Amphiphilic peptide-tagged N-cadherin forms radial glial-like fibers that enhance neuronal migration in injured brain and promote sensorimotor recovery.

The mammalian brain has very limited ability to regenerate lost neurons and recover function after injury. Promoting the migration of young neurons (neuroblasts) derived from endogenous neural stem cells using biomaterials is a new and promising approach to aid recovery of the brain after injury. However, the delivery of sufficient neuroblasts to distant injured sites is a major challenge because of the limited number of scaffold cells that are available to guide neuroblast migration. To address this issue, we have developed an amphiphilic peptide [(RADA)3-(RADG)] (mRADA)-tagged N-cadherin extracellular domain (Ncad-mRADA), which can remain in mRADA hydrogels and be injected into deep brain tissue to facilitate neuroblast migration. Migrating neuroblasts directly contacted the fiber-like Ncad-mRADA hydrogel and efficiently migrated toward an injured site in the striatum, a deep brain area. Furthermore, application of Ncad-mRADA to neonatal cortical brain injury efficiently promoted neuronal regeneration and functional recovery. These results demonstrate that self-assembling Ncad-mRADA peptides mimic both the function and structure of endogenous scaffold cells and provide a novel strategy for regenerative therapy.

The Intersection of Human and Veterinary Medicine-A Possible Direction towards the Improvement of Cell Therapy Protocols in the Treatment of Perianal Fistulas.

The effective treatment of perianal fistulizing Crohn's disease is still a challenge. Local administration of mesenchymal stromal cells (MSCs) is becoming a part of accepted treatment options. However, as a fledgling technique, it still can be optimized. A new trend in translational research, which is in line with "One Health" approach, bases on exploiting parallels between naturally occurring diseases affecting humans and companion animals. Canine anal furunculosis (AF) has been indicated as condition analogous to human perianal Crohn's disease (pCD). This narrative review provides the first comprehensive comparative analysis of these two diseases based on the published data. The paper also outlines the molecular mechanisms of action of MSCs which are likely to have a role in modulating the perianal fistula niche in humans, and refers them to the current knowledge on the immunomodulatory properties of canine MSCs. Generally, the pathogenesis of both diseases shares main determinants such as the presence of genetic predispositions, dysregulation of immune response and the relation to intestine microbiota. However, we also identified many aspects which should be further specified, such as determining the frequency of true fistulas formation in AF patients, elucidating the role of TNF and Th17 pathway in the pathogenesis of AF, or clarifying the role of epithelial-to-mesenchymal transition phenomenon in the formation of canine fistulae. Nevertheless, the available data support the hypothesis that the results from testing cell therapies in dogs with anal furunculosis have a significant translational value in optimizing MSC transplants procedures in pCD patients.

In silico Designing of an Epitope-Based Vaccine Against Common E. coli Pathotypes.

Escherichia coli (E. coli) is a Gram-negative bacterium that belongs to the family Enterobacteriaceae. While E. coli can stay as an innocuous resident in the digestive tract, it can cause a group of symptoms ranging from diarrhea to live threatening complications. Due to the increased rate of antibiotic resistance worldwide, the development of an effective vaccine against E. coli pathotypes is a major health priority. In this study, a reverse vaccinology approach along with immunoinformatics has been applied for the detection of potential antigens to develop an effective vaccine. Based on our screening of 5,155 proteins, we identified lipopolysaccharide assembly protein (LptD) and outer membrane protein assembly factor (BamA) as vaccine candidates for the current study. The conservancy of these proteins in the main E. coli pathotypes was assessed through BLASTp to make sure that the designed vaccine will be protective against major E. coli pathotypes. The multitope vaccine was constructed using cytotoxic T lymphocyte (CTL), helper T lymphocyte (HTL), and B cell lymphocyte (BCL) epitopes with suitable linkers and adjuvant. Following that, it was analyzed computationally where it was found to be antigenic, soluble, stable, and non-allergen. Additionally, the adopted docking study, as well as all-atom molecular dynamics simulation, illustrated the promising predicted affinity and free binding energy of this constructed vaccine against the human Toll-like receptor-4 (hTLR-4) dimeric state. In this regard, wet lab studies are required to prove the efficacy of the potential vaccine construct that demonstrated promising results through computational validation.

Applications of the amniotic membrane in tissue engineering and regeneration: the hundred-year challenge.

The amniotic membrane (Amnio-M) has various applications in regenerative medicine. It acts as a highly biocompatible natural scaffold and as a source of several types of stem cells and potent growth factors. It also serves as an effective nano-reservoir for drug delivery, thanks to its high entrapment properties. Over the past century, the use of the Amnio-M in the clinic has evolved from a simple sheet for topical applications for skin and corneal repair into more advanced forms, such as micronized dehydrated membrane, amniotic cytokine extract, and solubilized powder injections to regenerate muscles, cartilage, and tendons. This review highlights the development of the Amnio-M over the years and the implication of new and emerging nanotechnology to support expanding its use for tissue engineering and clinical applications.

Mesenchymal stem cell-based therapy and exosomes in COVID-19: current trends and prospects.

Novel coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus-2. The virus causes an exaggerated immune response, resulting in a cytokine storm and acute respiratory distress syndrome, the leading cause of COVID-19-related mortality and morbidity. So far, no therapies have succeeded in circumventing the exacerbated immune response or cytokine storm associated with COVID-19. Mesenchymal stem cells (MSCs), through their immunomodulatory and regenerative activities, mostly mediated by their paracrine effect and extracellular vesicle production, have therapeutic potential in many autoimmune, inflammatory, and degenerative diseases. In this paper, we review clinical studies on the use of MSCs for COVID-19 treatment, including the salutary effects of MSCs on the pathophysiology of COVID-19 and the immunomodulation of the cytokine storm. Ongoing clinical trial designs, cell sources, dose and administration, and populations are summarized, and the paracrine mode of benefit is discussed. We also offer suggestions for optimizing MSC-based therapies, including genetic engineering, strategies for cell surface modification, nanotechnology applications, and combination therapies.

Stem cell therapies for autoimmune hepatitis.

Autoimmune hepatitis is a chronic inflammatory hepatic disorder which may cause liver fibrosis. Appropriate treatment of autoimmune hepatitis is therefore important. Adult stem cells have been investigated as therapies for a variety of disorders in latest years. Hematopoietic stem cells (HSCs) were the first known adult stem cells (ASCs) and can give rise to all of the cell types in the blood and immune system. Originally, HSC transplantation was served as a therapy for hematological malignancies, but more recently researchers have found the treatment to have positive effects in autoimmune diseases such as multiple sclerosis. Mesenchymal stem cells (MSCs) are ASCs which can be extracted from different tissues, such as bone marrow, adipose tissue, umbilical cord, and dental pulp. MSCs interact with several immune response pathways either by direct cell-to-cell interactions or by the secretion of soluble factors. These characteristics make MSCs potentially valuable as a therapy for autoimmune diseases. Both ASC and ASC-derived exosomes have been investigated as a therapy for autoimmune hepatitis. This review aims to summarize studies focused on the effects of ASCs and their products on autoimmune hepatitis.

Admission SpO2 and ROX index predict outcome in patients with COVID-19.

BACKGROUND: This study aimed to evaluate the accuracy of pulse oximetry-derived oxygen saturation (SpO2) on room air, determined at hospital admission, as a predictor for the need for mechanical ventilatory support in patients with Coronavirus Disease-2019 (COVID-19). METHODS: In this retrospective observational study, demographic and clinical details of the patients were obtained during ICU admission. SpO2 and respiratory rate (RR) on room air were determined within the first 6 h of hospital admission. As all measurements were obtained on room air, we calculated the simplified respiratory rate­oxygenation (ROX) index by dividing the SpO2 by the RR. Based on the use of any assistance of mechanical ventilator (invasive or noninvasive), patients were divided into mechanical ventilation (MV) group and oxygen therapy group. The accuracy of the SpO2, CT score, and ROX index to predict the need to MV were determined using the Area under receiver operating curve (AUC). RESULTS: We included 72 critically ill patients who tested COVID-19-positive. SpO2 on the room air could predict any MV requirement (AUC [95% confidence interval]: 0.9 [0.8-0.96], sensitivity: 70%, specificity 100%, cut-off value ≤78%, P < 0.001). Within the MV group, the use of noninvasive ventilation (NIV) was successful in 37 (74%) patients, whereas 13 patients (26%) required endotracheal intubation. The cut-off ROX value for predicting early NIV failure was ≤1.4, with a sensitivity of 85%, a specificity of 86%, and an AUC of 0.86 (95% confidence interval of 0.73-0.94, P < 0.0001). CONCLUSIONS: A baseline SpO2 ≤78% is an excellent predictor of MV requirement with a positive predictive value of 100%. Moreover, the ROX index measured within the first 6 h of hospital admission is a good indicator of early NIV failure.

Upper gastrointestinal tract involvement in the management of bariatric patients in the Kingdom of Saudi Arabia.

BACKGROUND: Preoperative esophagogastroduodenoscopy (EGD) may affect the management of bariatric patients although this is not consistent universally. The present prospective study evaluated the effect of preoperative EGD findings in obese Saudi patients, including upper digestive symptoms (UDS) and comorbidities, on their planned surgery. METHODS: From January 2018 to May 2019, we conducted a 4-center retrospective observational study to evaluate the endoscopic findings among Saudi patients aged 18-65 years with a body mass index (BMI) >40 kg/m2. Preoperative data included UDS, comorbidities, Helicobacter pylori (H. pylori) infection assessed during a histopathological examination, and EGD findings. RESULTS: 717 patients underwent EGDs, and 432 underwent bariatric surgery. The mean BMI was 44.3±6.3 kg/m2, and the mean age was 27.8±11.8 years. The overall UDS prevalence was 49%, with the most frequent being gastroesophageal reflux disease 54% (387/717), followed by dyspepsia 44% (315/717). H. pylori infection was detected in 287/672 (42.4%) patients. The total percentage of patients with normal EGD was 36% (258/717). A delayed bariatric procedure was performed in 15% of the patients for the following reasons: 2.3% had large polyps of >1 cm (either hyperplastic or cystic polyps); 1.62% had esophagitis grade C and D based on the Los Angeles classification; 0.7% had Barrett's esophagus; and 5.7% had peptic ulcer disease. CONCLUSIONS: Our findings confirmed that obesity carries a profound health burden with a significant impact on health expenditures. Routine preoperative EGD in the obese Saudi population appears to be mandatory to identify factors that may change, delay, or postpone the bariatric procedure.

Peripheral perfusion index as a predictor of failed weaning from mechanical ventilation.

We hypothesized that impairment of peripheral perfusion index (PPI) during spontaneous breathing trial (SBT) might be predictive of weaning failure. We included 44 consecutive, adult, patients, who were scheduled for weaning after at least 48 h of invasive mechanical ventilation in this prospective observational study. Weaning failure was defined as failed SBT or reintubation within 48 h of extubation. PPI readings were obtained before initiation of the SBT, and every 5 min till the end of the SBT. PPI ratio was calculated at every time point as: PPI value/ baseline PPI. The primary outcome was the accuracy of PPI ratio at the end of the SBT in detecting failed weaning. Forty-three patients were available for the final analysis. Eighteen patients (42%) were considered failed weaning. PPI ratio was higher in patients with successful weaning compared to patients with failed weaning during the last 15 min of the SBT. PPI ratio at the end of SBT was higher in patients with successful weaning compared to patients with failed weaning. PPI ratio at the end of SBT had good predictive ability for weaning failure {area under receiver operating characteristic curve (95% confidence interval): 0.833(0.688-0.929), cutoff value ≤ 1.41}. The change in PPI during SBT is an independent predictor for re-intubation. PPI could be a useful tool for monitoring the patient response to SBT. Patients with successful weaning showed higher augmentation of PPI during the SBT compared to re-intubated patients. Failure of augmenting the PPI by 41% at the end of SBT could predict re-intubation with negative predictive value of 95%. Clinical trial identifier: NCT03974568. https://clinicaltrials.gov/ct2/show/NCT03974568?term=ahmed+hasanin&draw=3&rank=17.

Comparative study between human mesenchymal stem cells and etanercept as immunomodulatory agents in rat model of rheumatoid arthritis.

To compare human adipose tissue mesenchymal stem cells (AT-MSCs) and etanercept as immunomodulatory agents for collagen-induced arthritis (CIA). CIA was induced by rats' immunization with collagen type II (CII) in complete Freund's adjuvant in days 0 and 7. Before the onset of CIA, prevention group received five doses of AT-MSCS intraperitoneally. After establishment of arthritis, rats received either five doses of AT-MSCs or phosphate-buffered saline (PBS) intraperitoneally or six doses of etanercept subcutaneously. Clinical and histopathological evaluation were performed in all groups; serum levels of tumor necrosis factor-α (TNF-α), interleukin-10 (IL-10), and anti-collagen II were assessed by enzyme-linked immunosorbent assay (ELISA). A total percent of autoreactive T and regulatory T (Treg) cells were quantified using spleen immune histochemical analysis. AT-MSCs were able to delay the onset of CIA, suppress the ongoing clinical and histopathological signs, decrease serum levels of TNF-α and anti-collagen type II, and downregulate the autoreactive T cells as etanercept. AT-MSCs were more potent in Treg cells upregulation, producing high serum levels of IL10. AT-MSCs might have a therapeutic effect in CIA via their potency in immune cell education, representing an effective new promising approach in rheumatoid arthritis in human.

Splanchnic and systemic circulation cross talks: Implications for hemodynamic management of liver transplant recipients.

The interaction between splanchnic and systemic circulation has many hemodynamic and renal consequences during liver transplant. In a patient with liver cirrhosis, splanchnic vasodilatation causes arterial steal from the systemic circulation into the splanchnic bed, which decreases the effective blood volume. Moreover, rapid volume loading in these patients has less impact on the cardiac output because a higher proportion of infused fluid is shifted to the splanchnic area. Thus, in dissection phase, the traditional approach of volume loading to maintain intraoperative hemodynamic stability not only seems ineffective, but it may also aggravate surgical bleeding. Two approaches of volume therapy have been mentioned to maintain hemodynamic stability during liver transplantation: splanchnic volume reduction by volume restriction with or without phlebotomy to maintain low central venous pressure (CVP), and splanchnic decongestion using splanchnic vasoconstrictors. After reperfusion, an increase in the central blood volume was thought to have a deleterious effect on the new graft function; however, the precise central venous pressure value that causes hepatic congestion after reperfusion is unknown.