A computed tomographic analysis of frontal recess cells in association with the development of frontal sinusitis

Objective

This study was done to determine frontal recess anatomy cell variations and its association with frontal sinusitis. The incidence of frontal recess cells in the population, the presence of frontal recess cell variations in chronic rhinosinusitis and non-chronic rhinosinusitis and the association of frontal recess cell variation in the development of frontal sinusitis were also assessed.

Assessment of prophylactic heparin infusion as a safe preventative measure for thrombotic complications in pediatric kidney transplant recipients weighing <20 kg

Small‐sized kidney recipients (<20 kg) are at high risk of allograft vessel thrombosis. HP has been used to mitigate this risk but may infer an increase in bleeding risks. Therefore, we aim to determine whether HP is a safe means to prevent thrombosis in small kidney transplant patients by comparing those who have received HP and those who have NHP. A retrospective review of patients < 20 kg who underwent kidney transplant in our institution from 2000 to 2015 was performed. At our institution, unfractionated heparin 10 units/kg/hour is used as HP since 2009. Patients at increased risk of thrombosis (previous thrombosis, thrombophilia, nephrotic syndrome) and bleeding (therapeutic doses of heparin, diagnosis of coagulopathy) were excluded. Fifty‐six patients were identified (HP n = 46; NHP n = 10). Baseline demographics were similar between HP and NHP. There was no statistical difference in frequency of transfusions, surgical re‐exploration, or thrombotic events between HP and NHP. The HP group was more likely to have drop in Hb > 20 g/L (67.4% vs 30.0%, P = 0.038), and those who had drop in Hb > 20 g/L were more likely to also require pRBC transfusions (63.0% vs 20.0%, P = 0.017). Within the HP group, those who had bleeding complications had similar Hb levels as those who did not at baseline and post‐transplant. Outcomes in the HP and NHP groups were no different with respect to thrombosis or significant bleeding complications requiring pRBC transfusions or surgical intervention. Future prospective studies are required to investigate the balance of preventing thrombosis and risks of pRBC transfusions for small‐sized kidney recipients.     

Endothelial adhesion molecule expression is enhanced in the aorta and internal mammary artery of diabetic patients.

BACKGROUND: Diabetes mellitus is a major risk factor for the development of atherosclerosis but the mechanisms involved remain unclear. The expression of leukocyte adhesion molecules at the endothelial surface is a primary step in the recruitment of leukocytes into the intima and the subsequent development of lipid-containing foam cell lesions. Increased levels of circulating adhesion molecules have been identified in diabetic patients, but the distribution in the arterial wall has not been described. MATERIALS AND METHODS: Frozen sections were prepared from aorta and internal mammary artery obtained during bypass surgery from 12 diabetic and 16 nondiabetic patients. Adhesion molecules (intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and E-Selectin), macrophages, and lymphocytes were identified and quantified using immunohistochemistry; intimal hyperplasia was quantified. RESULTS: Endothelial expression of VCAM-1 and intimal smooth muscle cell expression of both VCAM-1 and ICAM-1 was increased in the aortas from diabetic patients. Intimal hyperplasia in aorta and internal mammary artery sections was significantly greater in diabetic tissue. Macrophages, T-lymphocytes, oil-red-O-stained lipid, glycated albumin, and glycated LDL were observed in the aorta of both diabetic and nondiabetic samples. CONCLUSIONS: The increased incidence of VCAM-1 and ICAM-1 in the aorta may partly explain the enhanced atherosclerosis associated with diabetes mellitus, and their presence in established lesions may emphasize their long-term importance. The intimal hyperplasia observed in the bypass vessel may be a contributing factor to the increased incidence of restenosis in diabetic patients.     

Adalimumab,a fully human anti–tumor necrosis factor α monoclonal antibody,for the treatment of rheumatoid arthritis in patients taking concomitant methotrexate: The ARMADA trial

Objective

To evaluate the efficacy and safety of adalimumab (D2E7), a fully human monoclonal tumor necrosis factor α antibody, in combination with methotrexate (MTX) in patients with active rheumatoid arthritis (RA) despite treatment with MTX.

Methods

In a 24‐week, randomized, double‐blind, placebo‐controlled study, 271 patients with active RA were randomly assigned to receive injections of adalimumab (20 mg, 40 mg, or 80 mg subcutaneously) or placebo every other week while continuing to take their long‐term stable dosage of MTX. The primary efficacy end point was the American College of Rheumatology criteria for 20% improvement (ACR20) at 24 weeks.

Results

An ACR20 response at week 24 was achieved by a significantly greater proportion of patients in the 20‐mg, 40‐mg, and 80‐mg adalimumab plus MTX groups (47.8%, 67.2%, and 65.8%, respectively) than in the placebo plus MTX group (14.5%) (P < 0.001). ACR50 response rates with the 20‐mg, 40‐mg, and 80‐mg adalimumab dosages (31.9%, 55.2%, and 42.5%, respectively) were significantly greater than that with placebo (8.1%) (P = 0.003, P < 0.001, and P < 0.001, respectively). The 40‐mg and 80‐mg doses of adalimumab were associated with an ACR70 response (26.9% and 19.2%, respectively) that was statistically significantly greater than that with placebo (4.8%) (P < 0.001 and P = 0.020). Responses were rapid, with the greatest proportion of adalimumab‐treated patients achieving an ACR20 response at the first scheduled visit (week 1). Adalimumab was safe and well tolerated; comparable numbers of adalimumab‐treated patients and placebo‐treated patients reported adverse events.

Conclusion

The addition of adalimumab at a dosage of 20 mg, 40 mg, or 80 mg administered subcutaneously every other week to long‐term MTX therapy in patients with active RA provided significant, rapid, and sustained improvement in disease activity over 24 weeks compared with MTX plus placebo.

     

p16(INK4a) is a useful marker of human papillomavirus integration allowing risk stratification for cervical malignancies

The present study was conducted to assess utility of p16(INK4a) immunopositivity as a surrogate marker for genomic integration of high-risk human papillomavirus infection (hrHPV). A total of 29 formalin-fixed, paraffin-embedded cervical low-grade squamous intraepithelial lesions (LSILs), 27 high-grade squamous intraepithelial lesions (HSILs) and 53 invasive squamous cell carcinomas (SCCs), histologically-diagnosed between 1st January 2006 to 31st December 2008 at the University of Malaya Medical Centre were stained for p16(INK4a) (CINtec Histology Kit (REF 9511, mtm laboratories AG, Heidelberg, Germany). Immunopositvity was defined as diffuse staining of the squamous cell cytoplasm and or nucleus (involving > 75% of the intraepithelial lesions or SCCs). Staining of basal and parabasal layers of intraepithelial lesions was pre-requisite. One (3.4%) LSIL, 24 (88.9%) HSIL and 46 (86.8%) SCC were p16(INK4a) immunopositive. All normal squamous epithelium did not express p16(INK4). p16(INK4a) expression was significantly lower (p<0.05) in LSIL compared with HSIL and SCC with no difference in expression between HSIL and SCC.The increased p16(INK4a) immunopositivity in HSIL and SCC appears in line with the integrated existence of the hrHPV and may provide more insightful information on risk of malignant transformation of cervical squamous intraepithelial lesions than mere hrHPV detection.     

Comparing 3 methods of monitoring gentamicin concentrations in patients with febrile neutropenia

Several nomograms and algorithms have been developed to individualize pharmacokinetic monitoring with their own advantages and disadvantages. This study compared 3 pharmacokinetic methods for predicting doses and monitoring of gentamicin in adult patients with febrile neutropenia. A retrospective study of 75 patients with febrile neutropenia was conducted at the Royal Adelaide Hospital, South Australia. Each patient received a course of once-daily gentamicin and had 2 sets of paired gentamicin serum concentrations. Pharmacokinetic parameters and ensuing doses were compared using 3 pharmacokinetic methods: (1) sequential Bayesian algorithm for gentamicin (SeBA-GEN), (2) Sawchuk-Zaske, and (3) Therapeutic Guidelines: Antibiotic Dose Adjustment Nomogram. The initial median (range) dose of gentamicin administered was 400 (240-640) mg. SeBA-GEN and Sawchuk-Zaske methods recommended similar subsequent gentamicin dose adjustments of 400 (280-640) mg and 400 (280-640) mg, respectively, whereas the Therapeutic Guidelines recommended an increase to 1390 (210-6240) mg. For the Therapeutic Guidelines, 64% of the patients had measured serum gentamicin concentrations that were below the minimum line of the nomogram for the first set of concentrations with only 32% of these patients having an area under the curve value of <70 mg h/L as calculated by SeBA-GEN. The SeBA-GEN method showed a statistically significant increase (68%-77%) in patients attaining the target concentrations of maximum concentration (Cmax) 15-25 mg/L compared with the Sawchuk-Zaske method (72%-65%, P > 0.05). SeBA-GEN also demonstrated greater precision in predicting the area under the curve, Cmax, and minimum concentration (Cmin) compared with the Sawchuk-Zaske method. In conclusion, as the Bayesian approach, that is, SeBA-GEN demonstrated greater precision and more patients were attaining the target concentrations, it is therefore the preferred method for gentamicin monitoring in patients with febrile neutropenia.     

Systematic protein-protein docking and molecular dynamics studies of HIV-1 gp120 and CD4: insights for new drug development

Background and the purpose of the study

The interactions between HIV-1 gp120 and mutated CD4 proteins were investigated in order to identify a lead structure for therapy based on competitive blocking of the HIV binding receptor for human T-cells. Crystal structures of HIV gp120-CD4 complexes reveal a close interaction of the virus receptor with CD4 Phe43, which is embedded in a pocket of the virus protein.

Methods

This study applies computer simulations to determine the best binding of amino acid 43 CD4 mutants to HIV gp120. Besides natural CD4, three mutants carrying alternate aromatic residues His, Trp and Tyr at position 43 were investigated. Several docking programs were applied on isolated proteins based on selected crystal structures of gp120-CD4 complexes, as well as a 5 ns molecular dynamics study on the protein complexes. The initial structures were minimized in Gromacs to avoid crystal packing effects, and then subjected to docking experiments using AutoDock4, FireDock, ClusPro and ZDock. In molecular dynamics, the Gibbs free binding energy was calculated for the gp120-CD4 complexes. The docking outputs were analyzed on energy within the respective docking software.

Results and conclusion

Visualization and hydrogen bonding analysis were performed using the Swiss-PdbViewer. Strong binding to HIV gp120 can be achieved with an extended aromatic group (Trp). However, the sterical demand of the interaction affects the binding kinetics. In conclusion, a ligand for an efficient blocking of HIV gp120 should involve an extended but conformational flexible aromatic group, i.e. a biphenyl. A docking study on biphenylalanine-43 confirms this expectation.