Implications of ALS-Associated Mutations on Biochemical and Biophysical Features of hSOD1 and Aggregation Formation.

One of the recognized motor neuron degenerative disorders is amyotrophic lateral sclerosis (ALS). By now, several mutations have been reported and linked to ALS patients, some of which are induced by mutations in the human superoxide dismutase (hSOD1) gene. The ALS-provoking mutations are located throughout the structure of hSOD1 and promote the propensity to aggregate. Despite numerous investigations, the underlying mechanism related to the toxicity of mutant hSOD1 through the gain of a toxic function is still vague. We surveyed two mutant forms of hSOD1 by removing and adding cysteine at positions 146 and 72, respectively, to investigate the biochemical characterization and amyloid formation. Our findings predicted the harmful and destabilizing impact of two SOD1 mutants using multiple programs. The specific activity of the wild-type form was about 1.42- and 1.92-fold higher than that of C146R and G72C mutants, respectively. Comparative structural studies using CD spectropolarimetry, and intrinsic and ANS fluorescence showed alterations in secondary structure content, exposure of hydrophobic patches, and structural compactness of WT-hSOD1 vs. mutants. We demonstrated that two mutants were able to promote amyloid-like aggregates under amyloid induction circumstances (50-mM Tris-HCl pH 7.4, 0.2-M KSCN, 50-mM DTT, 37 °C, 190 rpm). Monitoring aggregates were done using an enhancement in thioflavin T fluorescence and alterations in Congo red absorption. The mutants accelerated fibrillation with subsequently greater fluorescence amplitude and a shorter lag time compared to WT-SOD1. These findings support the aggregation of ALS-associated SOD1 mutants as an integral part of ALS pathology.

Maximum Surgical Blood Ordering Schedule in Common Pediatric Cardiac Surgeries in a Tertiary Center.

Background & Objective: Unnecessary pre-operative ordering of red blood cells (RBCs) in elective surgeries increases costs and waste of blood inventory. Maximum surgical blood order schedule (MSBOS) is a helpful strategy in the estimation of blood units needed for surgery and the prevention of overconsumption. In this study, an MSBOS for pediatric cardiac surgeries is designed. Methods: In this cross-sectional study, we included all pediatric patients who underwent elective cardiac surgery in Children's Medical Center in Tehran, Iran, from March 21, 2019, to September 22, 2019. Data consisted of the type of surgery and the number of blood units transfused and units cross-matched, based on which cross-match to transfusion ratio (CTR), the transfusion index (TI), and transfusion probability (T%) were calculated. Results: Overall 205 pediatric patients were included in the study. Four hundred and ten RBCs units were cross-matched, and 262 were transfused. The overall results of the CTR, T%, and TI for all the eight types of cardiac surgery were 1.56 (410/262), 76% (157/205), and 1.28 (262/205), respectively. The raw MSBOS for cardiac surgeries included ventricular septal defect, tetralogy of fallot, dextro-transposition of the great arteries, atrial septal defect, aortic coarctation, patent ductus arteriosus, pulmonary stenosis, and pacemaker insertion, which were 1.58, 1.03, 1.54, 1.66, 0.77, 0, 1.25, and 0 unit, respectively, and the figures were rounded up. Conclusion: Accurate MSBOS protocols reduce cross-match workload in laboratories, lead to the appropriate use of blood stocks with less wastage, save human and economic resources, and eventually, promote patient safety.

The Clinical, Diagnostic, Therapeutic, and Prognostic Characteristics of Brain Metastases in Prostate Cancer: A Systematic Review.

Aim: Prostate cancer (PCa) is the second most common nonskin malignancy and the second most common cause of cancer-related deaths in men. The most common site of metastasis in PCa is the axial skeleton which may lead to back pain or pathological fractures. Hematogenous spread to the brain and involvement of the central nervous system (CNS) are a rare occurrence. However, failed androgen deprivation therapy (ADT) may facilitate such a spread resulting in an advanced metastatic stage of PCa, which carries a poor prognosis. Methods: In this systematic review, we searched the PubMed, Scopus, and Web of Science online databases based on the PRISMA guideline and used all the medical subject headings (MeSH) in terms of the following search line: ("Brain Neoplasms" OR "Central Nervous System Neoplasms") and ("Prostatic Neoplasms" OR "Prostate"). Related studies were identified and reviewed. Results: A total of 59 eligible studies (902 patients) were included in this systematic review. In order to gain a deeper understanding, we extracted and presented the data from included articles based on clinical manifestations, diagnostic methods, therapeutic approaches, and prognostic status of PCa patients having BMs. Conclusion: We have demonstrated the current knowledge regarding the mechanism, clinical manifestations, diagnostic methods, therapeutic approaches, and prognosis of BMs in PCa. These data shed more light on the way to help clinicians and physicians to understand, diagnose, and manage BMs in PCa patients better.

Neuroblastoma: Essential genetic pathways and current therapeutic options.

Neuroblastoma is a very diverse pediatric tumor that starts from the neural crest, and it is responsible over more than 15% of all juvenile cancer deaths. Clinical signs and symptoms are highly dependent on tumor origin and spread. Bone, lymph nodes, liver, intracranial and orbital tissues, lungs, and the central nervous system are frequently involved in metastatic neuroblastoma. Neuroblastoma enhances with contrast in Computed Tomography (CT) scans as a solid heterogeneous mass which might invade to adjacent ipsilateral or contralateral lymph nodes, tissues, and vessels. Whereas the Magnetic Resonance Imaging (MRI) acquires an acceptable diagnostic accuracy for detection of spinal cord and musculoskeletal metastases. Lorlatinib, a novel ALK inhibitor designed to overcome this resistance, is currently being tested in the New Approaches to Neuroblastoma Therapy (NANT) consortium. Aurora kinase inhibitors have been reported to disrupt MYCN, which is particularly attractive considering the lack of direct inhibitors targeting this driver in neuroblastoma. Sorafenib, a RAF kinase inhibitor, and newer PI3K inhibitors are being tested in children with neuroblastoma in an attempt to block the RAS pathway. Despite various therapies including chemotherapy, radiotherapy, immunotherapy and autologous stem cell transplantation in different neuroblastoma risk groups, most patients undergo surgical removal of the tumoral mass. This review is aimed to summarize the updated knowledge about the neuroblastoma, pathogenesis, it's essential genetic pathways and the current available therapeutic options for neuroblastoma.

Assessing agro-environmental sustainability of intensive agricultural systems.

Sustainable production in water-scarce regions entails not to overshoot the sustainable blue water availability (BWA), which in turn requires addressing environmental flow requirements (EFRs). We explored the long-term effects of agricultural development, before (1984-1997) and during (1998-2018) the operation of the modern irrigation and drainage network of Tajan (TIDN), northern Iran, on the sustainability of blue water consumptions. A combination of different methods were applied to estimate hydrological EFRs of rivers, ab-bandans (traditional water reservoirs), and groundwater resources. Three major pollutants in the region's water resources, including nitrogen, phosphorus, and salinity, were used to estimate water quality EFR. Monthly agriculture water footprints (WFs) were calculated using the AquaCrop model, and then were compared with the region's BWA, which was calculated by subtracting monthly EFRs from monthly natural runoff. When WF exceeded BWA, the production system includes unsustainable water consumption. The EFR satisfaction of surface water decreased after TIDN operation by about 19%. Unmanaged nitrogen application and post-TIDN overexploitation of groundwater resulted in substantial increase in groundwater EFR violation. The TIDN led to more water consuming cropping pattern resulting in increased agricultural water consumption by about 73%. Overall, agricultural development in TIDN was beyond the capacity of the area, which resulted in up to about 167 MCM y-1 unsustainable blue water consumption. Based on the results, the new framework presented for assessing agro-environmental sustainability could assist managers and policy makers to modify agricultural systems according to environment resilience.

The Effect of Using In Vitro Fertilization (IVF) on Increasing the Prevalence of Craniosynostosis.

BACKGROUND: Craniosynostosis, a malformation caused by premature closure of one or more cranial sutures, is a rare congenital disability usually of unknown cause; however, it is often associated with assisted reproductive technology. Given the increasing prevalence of craniosynostosis and the use of the in vitro fertilization (IVF) method, the authors evaluated the association between IVF and the prevalence of craniosynostosis. METHODS: This retrospective study reviewed records of patients with nonsyndromic craniosynostosis who underwent surgery in Mofid Hospital, a tertiary children's hospital affiliated to Shahid Beheshti University of Medical Sciences, between 2010 and 2019. RESULTS: A total of 200 patients aged one month to 7 years old, were evaluated. Out of 200 patients, 43% were plagiocephalic, 39% trigonocephalic, 8.5% scaphocephalic, 8% brachiocephalic, and 1.5% were mixed. Nine (4.5%) patients had received clomiphene citrate. Eight (4%) mothers had become pregnant under IVF, and they all had used clomiphene citrate for ovulation stimulation. No use of artificial insemination was reported. Of the eight patients whose mother had become pregnant through IVF, three were trigonocephalic, and five were plagiocephalic. CONCLUSIONS: Without a control group, we are not able report the statistical results confirming or denying a link between craniosynostosis and infertility treatment. However, 4% prevalence of IVF use among craniosynostosis patients is significant. Further studies with a broader statistical community are suggested in this regard.

Cardiovascular manifestations in COVID-19 patients: A systematic review and meta-analysis.

Since December 2019, the COVID-19 pandemic has affected the global population, and one of the major causes of mortality in infected patients is cardiovascular diseases (CVDs).For this systematic review and meta-analysis, we systematically searched Google Scholar, Scopus, PubMed, Web of Science, and Cochrane databases for all articles published by April 2, 2020. Observational studies (cohort and cross-sectional designs) were included in this meta-analysis if they reported at least one of the related cardiovascular symptoms or laboratory findings in COVID-19 patients. Furthermore, we did not use any language, age, diagnostic COVID-19 criteria, and hospitalization criteria restrictions. The following keywords alone or in combination with OR and AND operators were used for searching the literature: "Wuhan coronavirus", "COVID-19", "coronavirus disease 2019", "SARS-CoV-2", "2019 novel coronavirus" "cardiovascular disease", "CVD", "hypertension", "systolic pressure", "dyspnea", "hemoptysis", and "arrhythmia". Study characteristics, exposure history, laboratory findings, clinical manifestations, and comorbidities were extracted from the retrieved articles. Sixteen studies were selected which involved 4754 patients, including 2103 female and 2639 male patients. Among clinical cardiac manifestations, chest pain and arrhythmia were found to have the highest incidence proportion. In addition, elevated lactate dehydrogenase (LDH) and D-dimer levels were the most common cardiovascular laboratory findings. Finally, hypertension, chronic heart failure, and coronary heart disease were the most frequently reported comorbidities. The findings suggest that COVID-19 can cause various cardiovascular symptoms and laboratory findings. It is also worth noting that cardiovascular comorbidities like hypertension have a notable prevalence among COVID-19 patients.

Treatment of palindromic rheumatism: A systematic review.

OBJECTIVES: Palindromic rheumatism (PR) characterised by self-resolving attacks of arthritis and peri-arthritis that may progress to other autoimmune connective tissue diseases (CTDs). The aim of this systematic review was to analyse the effectiveness of different treatments on PR. METHODS: Articles were collected from Cochrane, PubMed, Science Direct, Scopus, ProQuest, Ebsco, Google Scholar, MEDLINE and EMBASE. Search keywords were "palindromic rheumatism," "palindromic rheumatism and remission," "palindromic rheumatism and course," "palindromic rheumatism and prognosis," "palindromic rheumatism and treatment" and "palindromic rheumatism and therapy." The studies that were included met the following criteria: (a) adult patients aged ≥16 with PR; (b) being on treatment with medications defined as those that were developed for the treatment of inflammatory arthritis and (c) including outcome measures to evaluate the efficacy of the treatment including remission rate and progression to other diseases. RESULTS: Twenty-four studies met the inclusion criteria. Although case series and retrospective studies showed that conventional disease-modifying antirheumatic drugs (DMARDs) can control attacks of the disease, 15%-70% of patients with PR evolve to autoimmune CTDs during several years, despite treatment with DMARDs. A retrospective study showed that tight control strategy could control attacks of the disease and prevent its progression to RA. The evidence provided from available studies is insufficient to determine that DMARDs can prevent the progression of PR to autoimmune CTDs. CONCLUSION: Although case series and retrospective studies showed that DMARDs can control attacks of the disease, our review suggests that randomised clinical trials and prospective studies with adequate sample size are needed to prove that DMARDs can prevent progression of PR to autoimmune CTDs and which DMARDs are preferred for the treatment of PR.