Role of Matrix Metalloproteinase-9 in Neonatal Hypoxic-Ischemic Encephalopathy

BACKGROUND: Neonatal encephalopathy is a heterogeneous syndrome characterised by signs of central nervous system dysfunction in the newborn. Matrix metalloproteinase-9(MMP-9) increases the blood-brain barrier permeability, and their inhibitors can reduce its damage. MMP-9 has been implicated specifically in cerebral ischemia. AIM: To measure serum MMP-9 in neonatal hypoxic-ischemic encephalopathy and evaluate its correlation to the severity of early prediction and treatment. METHODS: its case-control study. The serum concentration of MMP-9 was determined by ELISA in 100 hypoxic neonates and 50 healthy neonates of matched age and sex who served as controls. RESULTS: In our present study the serum MMP-9 level was significantly higher at p = 0.0001 in hypoxic-ischemic full-term newborns (176.7 ± 68.7 ng/ml)as compared to control newborn (69.4 ± 34.85 ng/ml)and it was significantly higher at p = 0.0075 in hypoxic-ischemic preterm newborn (171.2 ± 132.9 ng/ml) when compared to control newborn (72.54 ± 36.74 ng/ml),also MMP-9 was significantly higher at Sarnat stage III at p = 0.0001. CONCLUSION: Serum MMP-9 level was significantly higher in hypoxic-ischemic newborns, and significantly increased with severity, so we suggest that serum MMP-9 level is important for predicting neurological sequel and severity in neonatal encephalopathy. &nbsp

Automatic Filtering and Substantiation of Drug Safety Signals

Drug safety issues pose serious health threats to the population and constitute a major cause of mortality worldwide. Due to the prominent implications to both public health and the pharmaceutical industry, it is of great importance to unravel the molecular mechanisms by which an adverse drug reaction can be potentially elicited. These mechanisms can be investigated by placing the pharmaco-epidemiologically detected adverse drug reaction in an information-rich context and by exploiting all currently available biomedical knowledge to substantiate it. We present a computational framework for the biological annotation of potential adverse drug reactions. First, the proposed framework investigates previous evidences on the drug-event association in the context of biomedical literature (signal filtering). Then, it seeks to provide a biological explanation (signal substantiation) by exploring mechanistic connections that might explain why a drug produces a specific adverse reaction. The mechanistic connections include the activity of the drug, related compounds and drug metabolites on protein targets, the association of protein targets to clinical events, and the annotation of proteins (both protein targets and proteins associated with clinical events) to biological pathways. Hence, the workflows for signal filtering and substantiation integrate modules for literature and database mining, in silico drug-target profiling, and analyses based on gene-disease networks and biological pathways. Application examples of these workflows carried out on selected cases of drug safety signals are discussed. The methodology and workflows presented offer a novel approach to explore the molecular mechanisms underlying adverse drug reactions

SARS-CoV-2 vaccination modelling for safe surgery to save lives: data from an international prospective cohort study

Background Preoperative SARS-CoV-2 vaccination could support safer elective surgery. Vaccine numbers are limited so this study aimed to inform their prioritization by modelling. Methods The primary outcome was the number needed to vaccinate (NNV) to prevent one COVID-19-related death in 1 year. NNVs were based on postoperative SARS-CoV-2 rates and mortality in an international cohort study (surgical patients), and community SARS-CoV-2 incidence and case fatality data (general population). NNV estimates were stratified by age (18–49, 50–69, 70 or more years) and type of surgery. Best- and worst-case scenarios were used to describe uncertainty. Results NNVs were more favourable in surgical patients than the general population. The most favourable NNVs were in patients aged 70 years or more needing cancer surgery (351; best case 196, worst case 816) or non-cancer surgery (733; best case 407, worst case 1664). Both exceeded the NNV in the general population (1840; best case 1196, worst case 3066). NNVs for surgical patients remained favourable at a range of SARS-CoV-2 incidence rates in sensitivity analysis modelling. Globally, prioritizing preoperative vaccination of patients needing elective surgery ahead of the general population could prevent an additional 58 687 (best case 115 007, worst case 20 177) COVID-19-related deaths in 1 year. Conclusion As global roll out of SARS-CoV-2 vaccination proceeds, patients needing elective surgery should be prioritized ahead of the general population

Azole carboxamide ribonucleoside triphosphates: Synthesis, site specific incorporation into RNA, and incorporation studies with bovine viral diarrhea virus (BVDV) polymerase

The introduction of modified nucleotides into RNA can greatly aid our understanding of its biological function. They can provide insight into the effects of individual nucleotides on RNA structure and on their interactions with RNA binding proteins. Approaches to synthesize RNA containing modified nucleotides are inefficient and limited.We have developed a method where modifications can be introduced at specific positions in RNA including the 3’- and the 5’-ends. This method involves the use of a combination of different enzymes including Therminator DNA polymerase, T4 DNA ligase, DNase I endonuclease, and RNase H ribonuclease and nucleoside triphosphates as substrates. The entire sequence of enzymatic reactions is carried out in a single Eppendorf ® tube omitting the need for intermediate purification steps. The modified nucleoside triphosphates used in this study were also tested as substrates for bovine viral diarrhea virus (BVDV) polymerase, a surrogate model for hepatitis C (HCV). The only FDA approved combination therapy for HCV is ribavirin plus α-interferon. The nucleoside analog, ribavirin, in its phosphorylated form can be misincorporated by the viral RdRp causing transition mutations. Viruses exist as a mixture of genetically heterogonous but related viral particles that have undergone the maximum amount of mutations without compromising viability or infectivity. Further increase in mutation rates can lead to loss of genetic information and production of non-viable and non-infectious viruses. Based on this concept, we decided to test a number of azole carboxamide ribonucleoside triphosphates (ribavirin analogs) as substrates for BVDV RdRp. They differ from ribavirin and among themselves in the placement of heteroatoms within the 5- membered heterocyclic ring. Pre-steady state kinetic parameters of incorporation of ribavirin analogs by BVDV RdRp were determined. Our studies revealed that analogs 3 and 4 are incorporated across from a G base in the template with rates comparable to the correct ribonucleotide (within 10-fold) and used by the polymerase more efficiently than a mismatch nucleotide. They can either act as viral mutagens if the polymerase can extend beyond them or as chain terminators if the polymerase cannot extend beyond them. In either case, these results establish those analogs as potential antiviral drugs

Structural Gizmos

Architects are visual learners. The Internet has enabled interactive learning tools that can be used to assist in visual thinking of structural concepts, especially at the introductory levels. Here, we propose a visual approach for understanding structures through a series of interactive learning modules, or “gizmos”. These gizmos, are the tools that the student may use to examine one structural concept at a time. Being interactive, they offer many more possibilities beyond what one static problem can show. The approach aims to enhance studentsi visual intuition, and hence understanding of structural concepts and the parameters affecting design. This paper will present selected structural gizmos, how they work, and how they can enhance structural education for architects

Comparative Study Between Great Saphenous Vein Endovenous Laser Ablation (EVLA) and Modified Haemodynamic Correction (CHIVA) as A Treatment for Varicose Veins

Varicose veins (VV) could be a handicapping condition which may lead to limb swelling, pain and venous stasis ulcer. Prevalence of VV could present from 1% to 73% and from 2% to 56% at women and men respectively. CHIVA has been developed through the last two decades and is currently the second most common surgical procedure for the operative management of VV. Endovenous laser treatment of GSV was approved by FDA in 2002 and SSV was approved in 2003. EVLT allows delivery of Laser energy directly into the blood vessel lumen. EVLT with a 1470-nm diode Laser system is clinically safe, feasible and well-tolerated technique without scar and allows people to return to their normal daily activities rapidly. In a prospective comparative study between January 2018 and January 2020, 40 patients from those attended the outpatient departments complaining from VV were assessed according to the CEAP classification and ultrasonic duplex and arranged into group I (CHIVA) and group II (EVLA). Both CHIVA operation and EVLA were performed under local anesthesia. Cases were reviewed regularly at the outpatient clinic for 6 months for recurrence and complications. The recurrence occurred at 2/20 and 0/20 at CHIVA and EVLA respectively.&nbsp

Comparative study between great saphenous vein endovenous laser ablation (EVLA) and modified haemodynamic correction (CHIVA) as a treatment for varicose veins

Varicose veins (VV) could be a handicapping condition which may lead to limb swelling, pain and venous stasis ulcer. Prevalence of VV could present from 1% to 73% and from 2% to 56% at women and men respectively. CHIVA has been developed through the last two decades and is currently the second most common surgical procedure for the operative management of VV. Endovenous laser treatment of GSV was approved by FDA in 2002 and SSV was approved in 2003. EVLT allows delivery of Laser energy directly into the blood vessel lumen. EVLT with a 1470-nm diode Laser system is clinically safe, feasible and well-tolerated technique without scar and allows people to return to their normal daily activities rapidly. In a prospective comparative study between January 2018 and January 2020, 40 patients from those attended the outpatient departments complaining from VV were assessed according to the CEAP classification and ultrasonic duplex and arranged into group I (CHIVA) and group II (EVLA). Both CHIVA operation and EVLA were performed under local anesthesia. Cases were reviewed regularly at the outpatient clinic for 6 months for recurrence and complications. The recurrence occurred at 2/20 and 0/20 at CHIVA and EVLA respectively.&nbsp