[Development and Optimization of Therapeutic Analogues of Anti-TNFα Antibody Infliximab].

Previously, we have reported the crystal structures of Fab fragment of Infliximab in complex with TNFα. The structurally identified epitope on TNFα revealed the mechanism of TNFα inhibition by partially overlapping with the TNFα-receptor interface and the possibility to optimize the binding affinity. In this study, we launched a screen of a phage display library to isolate novel anti-TNFα antibodies based on the infliximab epitope. To develop novel anti-TNFα antibodies, structural analysis, the phage display antibody isolation, step by step antibody optimization, CDR residues random mutagenesis, and binding affinity characterization were performed. One of the novel antibodies generated on the backbone of infliximab, Inf3D6, has the superior binding affinity to TNFα, thus, demonstrating the potential for structure guided optimization for improvement of existing antibody-based therapeutics.

[Predicting value of 2014 European guidelines risk prediction model for sudden cardiac death (HCM Risk-SCD) in Chinese patients with hypertrophic cardiomyopathy].

Objective: To evaluate the predicting value of the 2014 European Society of Cardiology (ESC) guidelines risk prediction model for sudden cardiac death (HCM Risk-SCD) in Chinese patients with hypertrophic cardiomyopathy (HCM), and to explore the predictors of adverse cardiovascular events in Chinese HCM patients. Methods: The study population consisted of a consecutive 207 HCM patients admitted in our center from October 2014 to October 2016. All patients were followed up to March 2017. The 5-year SCD probability of each patient was estimated using HCM Risk-SCD model based on electrocardiogram, echocardiography and cardiac magnetic resonance (CMR) examination results. The primary, second, and composite endpoints were recorded. The primary endpoint included SCD and appropriate ICD therapy, identical to the HCM Risk-SCD endpoint. The second endpoint included acute myocardial infarction, hospitalization for heart failure, thrombus embolism and end-stage HCM. The composite endpoint was either the primary or the second endpoint. Patients were divided into the 3 categories according to 5-year SCD probability assessed by HCM Risk-SCD model: low risk group<4%,intermediate risk group ≥4% to<6%, and high risk group≥6%. Results: (1) Prevalence of endpoints: All 207 HCM patients completed the follow-up (350 (230, 547) days). During follow-up, 8 (3.86%) patients reached the primary endpoints (3 cases of SCD, 3 cases of survival after defibrillation, and 2 cases of appropriate ICD discharge); 21 (10.14%) patients reached the second endpoints (1 case of acute myocardial infarction, 16 cases of heart failure hospitalization, 2 cases of thromboembolism, and 2 cases of end-stage HCM). (2) Predicting value of HCM Risk-SCD model: Patients with primary endpoints had higher prevalence of syncope and intermediate-high risk of 5-year SCD, as compared to those without primary endpoints (both P<0.05). (3) Predicting value of HCM Risk-SCD model: The low risk group included 122 patients (59%), the intermediate risk group 42 (20%), and the high risk group 43 (21%). There was a clear trend towards to higher heart rate, higher values of PTF(V1) and plane QRS-T angle, higher left ventricular mass index (LVMI), elevated maximal left ventricular outflow tract pressure gradient (LVOT-PGmax), enlarged left atrial dimension(LAD) and volume index (LAVI), reduced systolic mitral annular velocity (s'), and higher late gadolinium enhancement (LGE) volume and mass in patients with high risk of 5-year of SCD, as compared to those with low-intermediate risk (all P<0.05). Moreover, 5-year SCD probability was positively correlated with heart rate, plane QRS-T angle, LVMI, LAVI, LGE%, and negatively correlated with s'(r=0.161, P=0.019; r=0.669, P=0.001; r=0.206, P=0.004; r=0.284, P=0.000; r=0.351, P=0.000; r= -0.245, P=0.001; respectively). (4) LAD, LAVI, e' and s' were independent predictors for poor outcomes. HCM patients with LAD≥39 mm, LAVI≥49.6 ml/m(2), e'≤6.5 cm/s and s'≤6.6 cm/s were more likely to have adverse cardiovascular events (AUC 0.702, 95%CI 0.604-0.799, P=0.001; AUC 0.700, 95%CI 0.567-0.833, P=0.001; AUC 0.716, 95%CI 0.616-0.817, P=0.000; AUC 0.764, 95%CI 0.676-0.853, P=0.000,respectively). Conclusions: The HCM Risk-SCD model is of value in predicting SCD for Chinese HCM patients. The plane QRS-T angle and LGE% are the best predictors of 5-year SCD risk in Chinese HCM patients. Moreover, conventional echocardiographic parameters, including LAD, LAVI, e' and s', are useful to predict adverse cardiovascular events among Chinese HCM patients.

A study on the association of serum 1,5-anhydroglucitol levels and the hyperglycaemic excursions as measured by continuous glucose monitoring system among people with type 2 diabetes in China.

BACKGROUND: Blood glucose excursion is an important component of the glycaemic burden, but there are no indexes that can directly reflect them. The aim was to evaluate the values and significance of serum 1,5-anhydroglucitol (1,5-AG) in people with type 2 diabetes mellitus in China and to elucidate the relationship between 1,5-AG and traditional indexes of glycaemic excursions by continuous glucose monitoring. METHODS: A total of 576 healthy adults and 292 patients were included, and their 1,5-AG, fasting blood glucose and postprandial blood glucose and glycated haemoglobin were measured. For the 34 patients, their mean blood glucose, standard deviation of blood glucose, mean amplitude of glucose excursion, mean of daily differences, low blood glucose M-value index and the area under the curve for blood glucose above 180 mg/dL were calculated by use of a continuous glucose monitoring system. RESULTS: Serum levels of 1,5-AG among healthy adults were 28.44 ± 8.76 µg/mL with a significant gender bias rather than age bias. The 1,5-AG levels in people with type 2 diabetes mellitus were 4.57 ± 3.71 µg/mL, which were lower than those seen in the healthy adults. There was a correlation between 1,5-AG and glycated haemoglobin, fasting blood glucose, and postprandial blood glucose (r = -0.251, -0.195 and -0.349, respectively; all had p < 0.05). The continuous glucose monitoring system demonstrated that 1,5-AG presents a negative correlation with mean blood glucose, standard deviation of blood glucose, mean amplitude of glucose excursion and mean of daily differences for 7 days and with the area under the curve for blood glucose above 180 mg/dL on the third, fourth and seventh days. CONCLUSIONS: 1,5-AG may serve as a marker of hyperglycaemia and 7-day hyperglycaemic excursions as well as being a useful adjunct to glycated haemoglobin for blood glucose monitoring in patients with diabetes.

Local structure of layered oxide electrode materials for lithium-ion batteries.

Li-ion batteries are promising candidates for electrical energy storage in applications ranging from portable electronics to hybrid and electric vehicles. In this context, layered compounds in the Li(1+delta)(TM(x)Mn(1-x))(1-delta)O(2) family (TM = transition metal) have received much attention due to their high capacity and stability. In this Research News article we describe recent advances on structural characterization of Li-ion electrode materials using state-of-the-art electron microscopy. Direct evidence of the monoclinic nature of Li(2)MnO(3) has been provided. It has been demonstrated that differences in Z-contrast imaging between Li(2)MnO(3) and LiTMO(2) may be used to screen samples for phase separation in the 10-100 nm scale.

Probing particle structure in waterborne pressure-sensitive adhesives with atomic force microscopy.

There is a need to know the nanostructure of pressure-sensitive adhesive (PSA) films obtained from waterborne polymer colloids so that it can be correlated with properties. Intermittent-contact atomic force microscopy (AFM) of an acrylic waterborne PSA film identifies two components, which can be attributed to the polymer and the solids in the serum (mainly surfactant). It is found that when the average AFM tapping force, F(av), is relatively low, the polymer particles appear to be concave. But when F(av) is higher, the particles appear to have a convex shape. This observation is explained by a height artefact caused by differences in the indentation depths into the two components that vary with the tapping amplitude and F(av). To achieve the maximum contrast between the polymer and serum components, F(av) should be set such that the indentation depths are as different as possible. Unlike what is found for the height images, the phase contrast images of the PSA do not show a reversal in contrast over the range of tapping conditions applied. The phase images are thus reliable in distinguishing the two components of the PSA according to their viscoelastic properties. At the surface of films dried at room temperature, the serum component is found in localized regions within permanent depression into the film.

Acute jaundice in pregnancy: acute fatty liver or acute viral hepatitis?

In this case, the difficulty in differential diagnosis between acute viral hepatitis and acute fatty liver of pregnancy was analyzed. These 2 conditions often raise controversal question regarding the decision making on emergency anesthesia for cesarean section to avert complications and optimize management. The dilemma in which an anesthesiologist is put is whether to promise the anesthesia straightaway in the face of a demonstrable acute jaundice in pregnancy to advise a postponement of surgery until a turn for the better. In this embarrassing situation, the authors suggest that a postpronement of surgery is rational to observe the development during which both the mother and the fetus should be closely monitored. Once the necessity of a cesarean section outweighs the benefit of transitional conservative treatment, it should be performed immediately.

The effects of tramadol versus fentanyl in attenuating hemodynamic response following tracheal intubation.

BACKGROUND: Tramadol is a novel central acting analgesic. It has been used as a complement to general anesthesia and an effective agent for postoperative analgesia. However, the influence of tramadol on the hemodynamic response following laryngoscopy and tracheal intubation is less known. METHODS: Forty patients of both sexes, 16-50 year old, ASA physical status I or II, scheduled for elective surgery were randomly divided into equal groups in this prospective, double blind study. After obtaining the baseline data, the patient was given 3 micrograms/kg fentanyl (Group F) or 3 mg/kg tramadol (Group T). Then induction of anesthesia in a uniform and standardized manner was carried out by an anesthesiologist who was blind to the medication. The hemodynamic parameters were measured and recorded immediately after induction but prior to laryngoscopy, 3, 6, and 9 min after intubation, and before incision. We also observed any unusual effect in the postoperative care unit. Chi-square test, Student's t-test and paired t-test were used for statistical comparison. A P less than 0.05 was considered statistically significant. RESULTS: All patients had a successful induction and intubation. Differences in baseline values were not significant, nor were the differences in the values following induction. After laryngoscopy and intubation, heart rate increased significantly above the baseline level in both groups. The increase of heart rate was significantly more at 6 and 9 min (P < 0.05) and lasted longer in the tramadol group. After intubation, systolic, mean and diastolic arterial pressure (SAP, MAP, DAP) increased significantly above baseline in both groups too, except for DAP in fentanyl group. At 6 and 9 min, the MAP and DAP were significantly higher in tramadol than in fentanyl group (P < 0.05). Six patients in tramadol group had mild pain on injection of tramadol. CONCLUSIONS: When administered right before thiopental induction, 3 mg/kg tramadol did not display a better attenuation against the increase of hemodynamic profiles than did 3 micrograms/kg fentanyl following tracheal intubation.

Studies on urea biosensors based on immobilized corynebacterium glutamicum and their kinetic response processes.

Two novel biosensors for urea based on immobilized corynebacterium glutamicum 617 and corynebacterium glutamicum ATCC13032 in calcium alginate gel coupled with an ammonia gas-sensing electrode, were designed and constructed. Calibration plots of measured potential difference (mV) vs. log of urea concentration were linear in the range of 5.6 x 10(-5)-1.4 x 10(-2) and 5.6 x 10(-5)-1.1 x 10(-2) mol l(-1), with slopes of 59.2 and 61.3 mV per decade respectively, in pH 8.0, 0.1 mol l(-1) phosphate buffer solution at 30 degrees C. The relationship between the initial response velocity and the substrate concentration was also discussed. The results indicate that the kinetic response process of the reaction catalyzed by bacteria is similar to that by isolated enzyme. Using an Eadie-Hofstee plot, the apparent Michaelis constant K(m) and the maximum initial response velocity V(m) for urease in the immobilized bacterial membrane were determined. The two urea biosensors were successfully applied for the actual measurement of urea in urine and were relatively stable for 20 and 40 days respectively.

Nucleotide sequence analysis of the genomes of the MAV-PS1 and P-PAV isolates of barley yellow dwarf virus.

The MAV-PS1 and P-PAV isolates of barley yellow dwarf virus (BYDV) are serologically related, but not identical. Both are transmitted by the aphid Macrosiphum avenae, but P-PAV is also transmitted by Rhopalosiphum padi. To evaluate the basis for these and other differences, overlapping clones from cDNA libraries representing the genome of each isolate were characterized by restriction enzyme digestion and by hybridization, and subsequently sequenced. Each genome has six positive strand open reading frames (ORFs) which are similar to those identified from a BYDV isolate from Australia (Vic-PAV). The greatest diversity between MAV-PS1 and P-PAV sequences was found in ORFs located in the 3' half of the respective genomes, in particular ORFs 5 and 6, suggesting that these regions of the genome may be involved in the properties that differentiate MAV-PS1 and P-PAV. Sequence comparisons between P-PAV and Vic-PAV showed a high degree of identity in that all ORFs showed greater than 90% amino acid similarity, except ORF6 which had only 69% similarity.