Increased ß2-adrenergic signaling promotes fracture healing through callus neovascularization in mice.

Traumatic brain injury (TBI) leads to skeletal changes, including bone loss in the unfractured skeleton, and paradoxically accelerates healing of bone fractures; however, the mechanisms remain unclear. TBI is associated with a hyperadrenergic state characterized by increased norepinephrine release. Here, we identified the ß2-adrenergic receptor (ADRB2) as a mediator of skeletal changes in response to increased norepinephrine. In a murine model of femoral osteotomy combined with cortical impact brain injury, TBI was associated with ADRB2-dependent enhanced fracture healing compared with osteotomy alone. In the unfractured 12-week-old mouse skeleton, ADRB2 was required for TBI-induced decrease in bone formation and increased bone resorption. Adult 30-week-old mice had higher bone concentrations of norepinephrine, and ADRB2 expression was associated with decreased bone volume in the unfractured skeleton and better fracture healing in the injured skeleton. Norepinephrine stimulated expression of vascular endothelial growth factor A and calcitonin gene-related peptide-α (αCGRP) in periosteal cells through ADRB2, promoting formation of osteogenic type-H vessels in the fracture callus. Both ADRB2 and αCGRP were required for the beneficial effect of TBI on bone repair. Adult mice deficient in ADRB2 without TBI developed fracture nonunion despite high bone formation in uninjured bone. Blocking ADRB2 with propranolol impaired fracture healing in mice, whereas the ADRB2 agonist formoterol promoted fracture healing by regulating callus neovascularization. A retrospective cohort analysis of 72 patients with long bone fractures indicated improved callus formation in 36 patients treated with intravenous norepinephrine. These findings suggest that ADRB2 is a potential therapeutic target for promoting bone healing.

Safety and Efficacy of Bone Marrow and Adipose Tissue-Derived Mesenchymal Stem Cells for the Treatment of Ischemic Stroke: A Systematic Review.

Neurological diseases, including ischemic stroke, are considered a big challenge for public health due to their high prevalence and lack of definitive and effective treatments. Addressing these issues requires innovative therapeutic approaches and among the limited methods available, stem cells have shown promise in improving central nervous system repair by enhancing myelin regeneration and neuronal recovery. To advance this field of research, this systematic review aims to assess the safety and effectiveness of mesenchymal stem cells (MSCs) derived from both bone marrow and adipose tissue for the treatment of ischemic stroke. This study conducted a systematic review in the electronic databases PubMed, Scopus, Web of Science, Embase, ScienceDirect, and Google Scholar to assess the efficacy and safety of MSCs generated from bone marrow and adipose tissue for the treatment of ischemic stroke. It was extracted without a time limit until April 2023. The studies were then transferred to the information management program (EndNote) and duplicates were eliminated. The remaining studies were then examined using the entry and exit criteria and the 3 stages of primary, secondary, and qualitative evaluation, and finally, the results of the final studies were extracted. According to the initial search in the desired databases, 1028 possible related articles were identified and transferred to the information management software (EndNote). After removing 390 duplicate studies, 608 studies were excluded based on inclusion and exclusion criteria. Finally, 37 final studies were included in the systematic review process. Based on the investigations, it was evident that the administration of MSCs derived from both bone marrow and adipose tissue holds significant promise as an effective and safe treatment approach for ischemic stroke. The results consistently showed acceptable outcomes in the studies and this evidence can be recommended for the clinical application of this treatment. Also, the findings of this study report that the use of adipose tissue and bone marrow MSCs in the treatment of ischemic stroke can be used as a practical method.

Increased beta2-adrenergic signaling is a targetable stimulus essential for bone healing by promoting callus neovascularization.

Traumatic brain injury (TBI) is associated with a hyperadrenergic state and paradoxically causes systemic bone loss while accelerating fracture healing. Here, we identify the beta2-adrenergic receptor (Adrb2) as a central mediator of these skeletal manifestations. While the negative effects of TBI on the unfractured skeleton can be explained by the established impact of Adrb2 signaling on bone formation, Adrb2 promotes neovascularization of the fracture callus under conditions of high sympathetic tone, including TBI and advanced age. Mechanistically, norepinephrine stimulates the expression of Vegfa and Cgrp primarily in periosteal cells via Adrb2, both of which synergistically promote the formation of osteogenic type-H vessels in the fracture callus. Accordingly, the beneficial effect of TBI on bone repair is abolished in mice lacking Adrb2 or Cgrp, and aged Adrb2-deficient mice without TBI develop fracture nonunions despite high bone formation in uninjured bone. Pharmacologically, the Adrb2 antagonist propranolol impairs, and the agonist formoterol promotes fracture healing in aged mice by regulating callus neovascularization. Clinically, intravenous beta-adrenergic sympathomimetics are associated with improved callus formation in trauma patients with long bone fractures. Thus, Adrb2 is a novel target for promoting bone healing, and widely used beta-blockers may cause fracture nonunion under conditions of increased sympathetic tone.

The global prevalence of ADHD in children and adolescents: a systematic review and meta-analysis.

BACKGROUND: Attention-Deficit / Hyperactivity Disorder is a developmental neurological disorder that has three basic characteristics: Attention Deficit, Hyperactivity, and impulsivity. This study aimed to investigate the prevalence of ADHD in children and adolescents. METHODS: This investigation was carried out using the meta-analysis method under PRISMA guidelines. Until October 2020, the articles were gathered by scanning PubMed, Scopus, WOS, and Science Direct databases. The second version of Comprehensive Meta-Analysis software was used to run analyses after extracting data from chosen papers. At a significance level of 0.05, the I2 test was used to analyze study heterogeneity, and the Egger test was used to assess publication bias. RESULTS: This analysis includes 61 cross-sectional research, with 53 research used to determine the prevalence of ADHD in children, 7.6% of 96,907 children aged 3 to 12 years had ADHD (95% confidence interval: 6.1-9.4%), and 5.6% of teenagers aged 12 to 18 years have ADHD (95% confidence interval: 4.8-7%). The prevalence of ADHD in children and adolescents according to the DSM-V criterion is also higher than previous diagnostic criteria, according to studies. CONCLUSION: The findings of this study based on meta-analysis show the high prevalence of attention deficit hyperactivity disorder (ADHD). The findings of this study demonstrate the importance of management and policy in the treatment and control of ADHD in children and adolescents.

Global prevalence of congenital anencephaly: a comprehensive systematic review and meta-analysis.

BACKGROUND: Anencephaly is a fatal congenital anomaly characterized by the absence of brain hemispheres and cranial arch. Timely preventive measures can be taken by knowing the exact prevalence of this common neural tube defect; thus, carried out through systematic review and meta-analysis, the present study was conducted to determine the worldwide prevalence, incidence and mortality of anencephaly. METHODS: Cochran's seven-step instructions were used as the guideline. Having determined the research question and inclusion and exclusion criteria, we studied MagIran, SID, Science Direct, WoS, Web of Science, Medline (PubMed), Scopus, and Google Scholar databases. Moreover, the search strategy in each database included using all possible keyword combinations with the help of "AND" and "OR" operators with no time limit to 2021. The I2 test was used to calculate study heterogeneity, and Begg and Mazumdar rank correlation tests were employed to assess the publication bias. Data were analyzed by Comprehensive Meta-Analysis software (Version 2). RESULTS: In this study, the statements of Preferred Reporting Items for Systematic Reviews and Meta-Analyzes (PRISMA) were used. In the first stage, 1141 articles were found, of which 330 duplicate studies were omitted. 371 articles were deleted based on the inclusion and exclusion criteria by reviewing the title and abstract of the study. 58 articles were removed by reviewing the full text of the article because it was not relevant to the research. 360 studies with a sample size of 207,639,132 people were considered for the meta-analysis. Overall estimate of the prevalence, incidence and attenuation of anencephaly worldwide were 5.1 per ten thousand births (95% confidence interval 4.7-5.5 per ten thousand births), 8.3 per ten thousand births (95% confidence interval 5.5-9.9 per ten thousand births), 5.5 per ten thousand births (95% confidence interval 1.8-15 per ten thousand births) respectively the highest of which according to the subgroup analysis, belonged to the Australian continent with 8.6 per ten thousand births (95% confidence interval 7.7-9.5 per ten thousand births). CONCLUSION: The overall prevalence of anencephaly in the world is significant, indicating the urgent need for preventive and treating measures.

Anencephaly is a fatal congenital anomaly characterized by the absence of brain hemispheres and cranial arch. Cochran's seven-step instructions were used as the guideline. Having determined the research question and inclusion and exclusion criteria, we studied MagIran, SID, Science Direct, WoS, Web of Science, Medline (PubMed), Scopus, and Google Scholar databases. Moreover, the search strategy in each database included using all possible keyword combinations with the help of "AND" and "OR" operators with no time limit to 2021. Out of 1141 initial articles found, and after excluding repetitive ones in various databases and those irrelevant to inclusion criteria, 360 studies with a sample size of 207,639,132 people were considered for the meta-analysis. Overall estimate of the prevalence, incidence and attenuation of anencephaly worldwide were 5.1 per ten thousand births (95% confidence interval 4.7­5.5 per ten thousand births), 8.3 per ten thousand births (95% confidence interval 5.5­9.9 per ten thousand births), 5.5 per ten thousand births (95% confidence interval 1.8­15 per ten thousand births) respectively the highest of which according to the subgroup analysis, belonged to the Australian continent with 8.6 per ten thousand births (95% confidence interval 7.7­9.5 per ten thousand births). The overall prevalence of anencephaly in the world is significant, indicating the urgent need for preventive and treating measures.

The effect of exercise on balance in patients with stroke, Parkinson, and multiple sclerosis: a systematic review and meta-analysis of clinical trials.

BACKGROUND: Stroke, Parkinson, and multiple sclerosis are a range of diseases affecting the nervous system and show balance impairments due to damage of the balance control system. Many early articles have been published on the effect of exercise on balance in patients suffering from neuromuscular diseases. However, a comprehensive study showing a clear result of these three diseases was not found. Hence, the purpose of the present meta-analysis and systematic review is to determine the effect of exercise on balance in people with stroke, Parkinson, and multiple sclerosis. METHODS: According to the PRISMA 2009 multi-step instructions, keywords related to the purpose of the research were browsed in the MeSH browser databases; IranDoc, MagIran, IranMedex, SID, ScienceDirect, Web of Science (WoS), ProQuest, Medline (PubMed), Scopus, and Google Scholar were searched to extract articles published in Persian and English language. The search process for retrieving the articles in the sources mentioned from January 01, 2000, to December 30, 2020, was done. The heterogeneity index of the studies was determined using the I2 test. Given the heterogeneity, the random-effects model was used to combine the articles and the results. RESULTS: Initially, 7067 articles were found, but after removing duplicate and irrelevant articles, 96 clinical trials with a sample size of the intervention group of 1760 people were included in the study. As a result of the articles' composition, the mean balance score index after exercise in the intervention group showed a significant increase of 0.67 ± 0.12 of the unit (P˂0.01). The highest rate of increase in the balance score after the intervention was reported in patients with myelomeningocele with 1.66 ± 0.3 unit (P˂0.01). CONCLUSION: Considering the positive effect of using exercise on increasing the balance in patients with stroke, Parkinson, and multiple sclerosis, it is recommended that health care providers implement a regular exercise program to improve the condition of these patients.

Future Perspectives in Spinal Cord Repair: Brain as Saviour? TSCI with Concurrent TBI: Pathophysiological Interaction and Impact on MSC Treatment.

Traumatic spinal cord injury (TSCI), commonly caused by high energy trauma in young active patients, is frequently accompanied by traumatic brain injury (TBI). Although combined trauma results in inferior clinical outcomes and a higher mortality rate, the understanding of the pathophysiological interaction of co-occurring TSCI and TBI remains limited. This review provides a detailed overview of the local and systemic alterations due to TSCI and TBI, which severely affect the autonomic and sensory nervous system, immune response, the blood-brain and spinal cord barrier, local perfusion, endocrine homeostasis, posttraumatic metabolism, and circadian rhythm. Because currently developed mesenchymal stem cell (MSC)-based therapeutic strategies for TSCI provide only mild benefit, this review raises awareness of the impact of TSCI-TBI interaction on TSCI pathophysiology and MSC treatment. Therefore, we propose that unravelling the underlying pathophysiology of TSCI with concomitant TBI will reveal promising pharmacological targets and therapeutic strategies for regenerative therapies, further improving MSC therapy.

How could perfluorocarbon affect cytokine storm and angiogenesis in coronavirus disease 2019 (COVID-19): role of hypoxia-inducible factor 1α.

Coronavirus disease 2019 (COVID-19) pandemic is still a world-class challenge. Inflammation, especially its severe form with excess release of pro-inflammatory cytokines (cytokine storm) which is a life-threatening condition, is among the most important suspects involved in COVID-19 pathogenesis. It has been shown that cytokine storm could cause notable morbidities such as acute respiratory distress syndrome (ARDS) which leads to hypoxia which is significantly associated with mortality of patients with COVID-19. Hypoxia-inducible factor 1α (HIF-1α) which activates following ARDS-induced hypoxia plays a crucial role in pathogenesis of cytokine storm. The expression of tumor necrosis factor α (TNF-α), interleukin 1 ß (IL-1ß), and IL-6 which are key elements of cytokine storm are by nuclear factor κß (NFκB). Interestingly, during the hypoxia, HIF-1α activates NFκB to induce expression of pro-angiogenic and pro-inflammatory factors. These released factors starts a autocrine/paracrine loop and causes deterioration of their etiological pathways of expression: cytokine storm and ARDS. To sum up, it seems HIF-1α is an important target to hit to ameliorate the mentioned pathways. Herein, we suggest perfluorocarbons (PFCs) which are among the organofluorine compounds as a possible co-treatment to reduce hypoxemia and then hypoxia. These substances are known for their high gas solving potential that make them able to be used as a synthetic artificial blood product. Due to the potential of PFCs to affect the fountain of important physiopathological pathway such as inflammation a hypoxia through affecting NFκB, they could be considered as multi-target co-treatment for ARD individuals with COVID-19. It is highly suggested to evaluate this hypothesis in following researches.