H5N1 Clade 2.2 Polymorphism Tracing Identifies Influenza Recombination and Potential Vaccine Targets

Highly pathogenic Influenza A H5N1 was first identified in Guangdong Province in 1996, followed by human cases in Hong Kong in 1997 1. The number of confirmed human cases now exceeds 300 and the associated Case Fatality Rate exceeds 60% 2. The genetic diversity of the serotype continues to increase. Four distinct clades or sub-clades have been linked to human cases 3.4. The gradual genetic changes identified in the sub-clades have been attributed to copy errors by viral encoded polymerases that lack an editing function, thereby resulting in antigenic drift 5. We traced polymorphism acquisition in Clade 2.2 sequences. We report here the concurrent acquisition of the same polymorphism by multiple, genetically distinct, Clade 2.2 sub-clades in Egypt, Russia and Ghana. These changes are not easily explained by the current theory of “random mutation” through copy error, and are more easily explained by recombination with a common source. This conclusion is supported by additional polymorphisms shared by Clade 2.2 isolates in Egypt, Nigeria and Germany including aggregation of regional polymorphisms from each of these areas into a single Nigerian human hemagglutinin gene

The binding and activation of the glucagon-like peptide-1 receptor by exendin-4

Background and purpose Exendin-4 (EX4) has the same physiological properties as glucagon-like peptide-1 (7-36)amide (GLP-1). EX4 has 50% identity with GLP-1, with an extra nine amino acids at its C-terminus. The two peptides mediate their functions through coupling to the glucagon like peptide-1 receptor (GLP-1R) with similar affinity and potency. Unlike N-terminally truncated GLP-1, (GLP-1(15-36)amide), the equivalently truncated EX4(9-39) binds GLP-1R without significant loss of affinity; furthermore, GLP-1(15-36) is a partial agonist while EX4(9-39) is an antagonist. Previous binding analysis of either N or C-terminally truncated EX4 at rGLP-1R suggested that the residues responsible for its extra affinity are at its C-terminus, EX4 residues 31-39. Crystal structures supported by mutagenesis showed similar interactions of both GLP-1 and EX4 at the isolated N-terminal domain of human GLP-1R (hGLP-1R-NTD) apart from a subtle hydrogen bond between Ser32 in EX4 and Glu68 in hGLP-1R-NTD. Experimental approach The affinities and activities of GLP-1, EX4 and various analogues were measured at human and rat GLP-1R (hGLP-1R and rGLP-1R, respectively) and various receptor variants. Computer models, molecular dynamics coupled with in silico mutagenesis, were used to model and interpret the data. Key results The membrane-tethered NTDs of hGLP-1R displayed similar affinity for GLP-1 and EX4 in contrast to previous studies using the soluble isolated domain. The selective high affinity at rGLP-1R and the rGLP-1R-like mutant hGLP-1R-Glu68Asp for EX4(9–39) over EX4(9–30) was due to Ser32 in the ligand. This selectivity was not observed with hGLP-1R and the hGLP-1R-like mutant rGLP-1R-Asp68Glu. Gly16-EX4(9–30) was an agonist for rGLP-1R and hGLP-1R-Glu68Asp but was an antagonist for hGLP-1R and rGLP-1R-Asp68Glu. Glu22-GLP-1(15-36) was a partial agonist for all tested receptors. Insertion of (EEEAVRL) of EX4 instead of their equivalent sequence in GLP-1(15-36) prevented its activity and did not enhance its affinity. Substitution of Ser32 in EX4 by similar hydrogen bond donor amino acids did not enhance EX4 affinity or potency. Conclusions and implications GLP-1 and EX4 bind to the NTD of hGLP-1R with similar affinity. A hydrogen bond between Ser32 of EX4 and Asp68 of rGLP-1R is responsible for the improved affinity of EX4 and can play a role in the antagonist/agonist switch of Gly16-EX4(9–30) at the rat receptor. The discovery of the novel antagonist/agonist switch suggests a new mechanism of activation by GLP-1 which does not require its extreme N-terminal residues.EThOS - Electronic Theses Online ServiceGBUnited Kingdo

EFFECT OF OILS, SURFACTANTS AND COSURFACTANTS ON PHASE BEHAVIOR AND PHYSICOCHEMICAL PROPERTIES OF SELF-NANOEMULSIFYING DRUG DELIVERY SYSTEM (SNEDDS) FOR IRBESARTAN AND OLMESARTAN

Objective: The main purpose of this study was to optimize the different conditions for the preparation of self-nanoemulsifying drug delivery system (SNEDDS) for both Irbesartan (IRB) and Olmesartan (OLM). Methods: Based on solubility study and emulsification efficiency, Preliminary investigations of various oils, surfactants and cosurfactants were carried out for selection of the proper SNEDDS ingredients. Pseudoternary phase diagrams were then plotted using series of concentrations to obtain optimum SNEDDS components that identify the efficient self-nanoemulsifying region. Sixteen unloaded SNEEDS formulae were prepared using Capryol 90, Cremophor RH 40 and Transcutol HP as oil, surfactant and cosurfactant respectively. The prepared SNEDDS were evaluated for self-nanoemulsification time, the effect of dilution (with different volumes at different pH values), optical clarity, viscosity, droplet size analysis as well as the polydispersity index (PDI). SNEDDS formulae were also evaluated for thermodynamic stability and zeta potential to confirm the stability of the prepared SNEDDS. Results: The results showed that the mean droplet size of all reconstituted SNEDDS was found to be in the nanometric range (<100 nm) and showed optimum PDI values. All formulae also showed rapid emulsification time, good optical clarity and found to be highly stable. Formulae with the smallest particle size, lowest emulsification time, best optical clarity and robust to dilution and pH change were selected to be loaded with IRB and OLM for further study. Conclusion: It was concluded that the prepared self-emulsified prototype was ready to incorporate many poorly soluble drugs in order to improve their solubility as well as bioavailability profile. Keywords: Irbesartan, Olmesartan, Self-nanoemulsifying drug delivery system (SNEDDS), Capryol 90, Cremophor RH 40 and Transcutol HP

EFFECT OF ADDITIVES ON IN-VITRO RELEASE OF ORODISPERSIBLE DOSAGE FORM

Objective: The aim of this investigation was to prepare orodispersible tablets of meloxicam using various concentrations of superdisintegrants like Ac-DI-Sol, crospovidone, sodium starch glycolate by the direct compression method. Methods: Nine formulae of Meloxicam orodispersible tablets were prepared. These tablets were evaluated for their drug content, weight variation, friability, hardness, wetting time, In-vitro disintegration time and drug release.Results: All the formulation exhibited hardness between 4.21–4.55 kg/cm2. The tablets were disintegrating within 8.3 to 21.9 sec. Dissolution studies revealed that formula containing 7.5 % sodium starch glycolate showed 100% of drug release, at the end of six minutes. Among the formulated tablets, formula F9 containing 7.5 % sodium starch glycolate showed superior organoleptic properties along with excellent In-vitro disintegration time and drug release as compared to other formulae. The concentration of superdisintegrants had an effect on disintegration time and In-vitro drug dissolution whereas hardness and friability of resulting tablets were found to be independent of disintegrant concentration. It was concluded that the superdisintegrants addition technique is a useful method for preparing orodispersible tablets by the direct compression method.Â

Impact of heavy metals on the food web in the Mediterranean lagoon, Lake Burullus, Egypt

Research on the impact of heavy metals and their accumulation in ecosystem elements of Lake Burullus is still scarce. Therefore, this study focuses on the relationship between the levels of heavy metals in the lake water, plankton communities and Nile tilapia (Oreochromis niloticus). The mean annual concentrations of Fe, Zn, Cu, Mn, Pb and Cd in water and fish samples were 527.8, 366.7, 162.6, 137.3, 119.8 and 3.6 μg l−1, and 70.8, 43.6, 8.05, 1.2, 0.14 and 0.045 µg g−1 dry weight (d.w.), respectively. The study demonstrated the relationship between the accumulation of metals in fish muscles and their levels in the lake water (p < 0.05; r = 0.7–0.9), with the metal content in O. niloticus muscles being mostly below the permissible limits. The obtained results showed that the levels of the metals in the lake water are not correlated with phytoplankton and zooplankton, and their groups, except copper and zinc, are negatively correlated with phytoplankton (r = −0.45 and −0.58, respectively). The study concluded that the concentrations of the analyzed metals in Lake Burullus did not reach the effective levels that would have a significant impact on the distribution of phytoplankton and zooplankton, or a hazardous effect on O. niloticus and its safety for human consumption.Research on the impact of heavy metals and their accumulation in ecosystem elements of Lake Burullus is still scarce. Therefore, this study focuses on the relationship between the levels of heavy metals in the lake water, plankton communities and Nile tilapia (Oreochromis niloticus). The mean annual concentrations of Fe, Zn, Cu, Mn, Pb and Cd in water and fish samples were 527.8, 366.7, 162.6, 137.3, 119.8 and 3.6 μg l−1, and 70.8, 43.6, 8.05, 1.2, 0.14 and 0.045 µg g−1 dry weight (d.w.), respectively. The study demonstrated the relationship between the accumulation of metals in fish muscles and their levels in the lake water (p < 0.05; r = 0.7–0.9), with the metal content in O. niloticus muscles being mostly below the permissible limits. The obtained results showed that the levels of the metals in the lake water are not correlated with phytoplankton and zooplankton, and their groups, except copper and zinc, are negatively correlated with phytoplankton (r = −0.45 and −0.58, respectively). The study concluded that the concentrations of the analyzed metals in Lake Burullus did not reach the effective levels that would have a significant impact on the distribution of phytoplankton and zooplankton, or a hazardous effect on O. niloticus and its safety for human consumption

Indoor positioning system based on magnetic fingerprinting-images

In latest years, indoor positioning techniques have gained much attention, because of the absence GPS signal, so this paper shows a low priced mobile mapping system through using the advantages of integrating inertial navigation with smartphone sensors information concerned to a previous training phase with a magnetic map properly computed to more accurate positioning. Thus, areal online data sets were compiled through the use of ultra wide band to furnish an accurate positioning on the whole area of test and compute a trajectory used as a reference. Then, the use of the pedestrian dead reckoning based approach and IMU help to supply external information from the Wi-Fi signal that is used to exploit the received signal strength path loss, which is possibly used to assess the space between the device and access points. Furthermore, these real online data sets have been processed using Matlab to illustrate the different paths of the area of test. Also, using all RSS for every path line, different images were created. Finally, the positioning efficiency that is possible to be realized using information from IMU and UWB accelerated the fingerprinting training phase. So, the graphical analysis is used to summarize the results that match the closest path to the true path using mutual information

Surgical site infection after gastrointestinal surgery in high-income, middle-income, and low-income countries: a prospective, international, multicentre cohort study

Background: Surgical site infection (SSI) is one of the most common infections associated with health care, but its importance as a global health priority is not fully understood. We quantified the burden of SSI after gastrointestinal surgery in countries in all parts of the world. Methods: This international, prospective, multicentre cohort study included consecutive patients undergoing elective or emergency gastrointestinal resection within 2-week time periods at any health-care facility in any country. Countries with participating centres were stratified into high-income, middle-income, and low-income groups according to the UN's Human Development Index (HDI). Data variables from the GlobalSurg 1 study and other studies that have been found to affect the likelihood of SSI were entered into risk adjustment models. The primary outcome measure was the 30-day SSI incidence (defined by US Centers for Disease Control and Prevention criteria for superficial and deep incisional SSI). Relationships with explanatory variables were examined using Bayesian multilevel logistic regression models. This trial is registered with ClinicalTrials.gov, number NCT02662231. Findings: Between Jan 4, 2016, and July 31, 2016, 13 265 records were submitted for analysis. 12 539 patients from 343 hospitals in 66 countries were included. 7339 (58·5%) patient were from high-HDI countries (193 hospitals in 30 countries), 3918 (31·2%) patients were from middle-HDI countries (82 hospitals in 18 countries), and 1282 (10·2%) patients were from low-HDI countries (68 hospitals in 18 countries). In total, 1538 (12·3%) patients had SSI within 30 days of surgery. The incidence of SSI varied between countries with high (691 [9·4%] of 7339 patients), middle (549 [14·0%] of 3918 patients), and low (298 [23·2%] of 1282) HDI (p < 0·001). The highest SSI incidence in each HDI group was after dirty surgery (102 [17·8%] of 574 patients in high-HDI countries; 74 [31·4%] of 236 patients in middle-HDI countries; 72 [39·8%] of 181 patients in low-HDI countries). Following risk factor adjustment, patients in low-HDI countries were at greatest risk of SSI (adjusted odds ratio 1·60, 95% credible interval 1·05–2·37; p=0·030). 132 (21·6%) of 610 patients with an SSI and a microbiology culture result had an infection that was resistant to the prophylactic antibiotic used. Resistant infections were detected in 49 (16·6%) of 295 patients in high-HDI countries, in 37 (19·8%) of 187 patients in middle-HDI countries, and in 46 (35·9%) of 128 patients in low-HDI countries (p < 0·001). Interpretation: Countries with a low HDI carry a disproportionately greater burden of SSI than countries with a middle or high HDI and might have higher rates of antibiotic resistance. In view of WHO recommendations on SSI prevention that highlight the absence of high-quality interventional research, urgent, pragmatic, randomised trials based in LMICs are needed to assess measures aiming to reduce this preventable complication

Laparoscopy in management of appendicitis in high-, middle-, and low-income countries: a multicenter, prospective, cohort study.

BACKGROUND: Appendicitis is the most common abdominal surgical emergency worldwide. Differences between high- and low-income settings in the availability of laparoscopic appendectomy, alternative management choices, and outcomes are poorly described. The aim was to identify variation in surgical management and outcomes of appendicitis within low-, middle-, and high-Human Development Index (HDI) countries worldwide. METHODS: This is a multicenter, international prospective cohort study. Consecutive sampling of patients undergoing emergency appendectomy over 6 months was conducted. Follow-up lasted 30 days. RESULTS: 4546 patients from 52 countries underwent appendectomy (2499 high-, 1540 middle-, and 507 low-HDI groups). Surgical site infection (SSI) rates were higher in low-HDI (OR 2.57, 95% CI 1.33-4.99, p = 0.005) but not middle-HDI countries (OR 1.38, 95% CI 0.76-2.52, p = 0.291), compared with high-HDI countries after adjustment. A laparoscopic approach was common in high-HDI countries (1693/2499, 67.7%), but infrequent in low-HDI (41/507, 8.1%) and middle-HDI (132/1540, 8.6%) groups. After accounting for case-mix, laparoscopy was still associated with fewer overall complications (OR 0.55, 95% CI 0.42-0.71, p < 0.001) and SSIs (OR 0.22, 95% CI 0.14-0.33, p < 0.001). In propensity-score matched groups within low-/middle-HDI countries, laparoscopy was still associated with fewer overall complications (OR 0.23 95% CI 0.11-0.44) and SSI (OR 0.21 95% CI 0.09-0.45). CONCLUSION: A laparoscopic approach is associated with better outcomes and availability appears to differ by country HDI. Despite the profound clinical, operational, and financial barriers to its widespread introduction, laparoscopy could significantly improve outcomes for patients in low-resource environments. TRIAL REGISTRATION: NCT02179112

Impact of ginger powder (Zingiber officinale) supplementation on the performance, biochemical parameters, antioxidant status, and rumen fermentation in Ossimi rams

Background and Aim: Ginger (Zingiber officinale) has great potential as a growth promoter and immunostimulant in ruminant nutrition. This study assessed the impact of ginger powder supplementation on Ossimi rams’ rumen fermentation, biochemical parameters, and antioxidant levels. Materials and Methods: Fifteen Ossimi rams, aged 10 ± 1.3 months and weighing 30 ± 1.5 kg. Rams were randomly divided into three experimental groups: The control group (G1) received standard feed, while ginger powder (5 g and 7 g/kg body weight [BW] for G2 and G3, respectively) mixed in water was administered to groups G2 and G3 before their standard feed. Results: The control group recorded higher dry matter (DM) intake values (p < 0.05) than the ginger-treated groups. The ginger-treated groups showed superiority (p < 0.05) in weight gain and feed conversion compared to the control group. The digestion coefficients of DM, crude protein, and crude fiber were significantly (p < 0.05) increased by a high dose (7 g/Kg BW) of ginger supplementation, whereas organic matter, ether extract, and nitrogen-free extract digestibility remained unchanged. Compared to the control group, the rams given 5 g of ginger had significantly less (p < 0.05) total protein and globulin in their serum, but the rams given 7 g of ginger had significantly more (p < 0.05) of these proteins. In the ginger groups, these levels were significantly (p < 0.01) lower than those in the control group for serum creatinine, uric acid, urea, total lipids, triglycerides, total cholesterol, glucose, serum alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, and gamma-glutamyl transferase. Rams given ginger had significant growth hormone, insulin-like growth factor-1, total superoxide dismutase, GSH-Px, TAC, immunoglobulin (Ig) A, and IgG enhancement (p < 0.01), and a decrease (p < 0.01) in malondialdehyde concentration compared to the control group. Significant increases in total short-chain volatile fatty acids, acetic, propionic, and isovaleric acids (p < 0.05), and significant decreases in NH3N and protozoa (p < 0.01). Conclusion: Ginger powder (5 g and 7 g) can improve growth, immune responses, antioxidant status, and ruminal parameters in rams. Further study is needed to evaluate the effect of ginger on different types of animals (cow, buffalo, and goat) to develop new feed additives