Two-Generation Confirmation of Crown-Size Body-Size Relationships in Human Beings

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/67200/2/10.1177_00220345680470064301.pd

CFD Assessment of Respiratory Drug Delivery Efficiency in Adults and Improvements Using Controlled Condensational Growth

Pharmaceutical aerosols provide a number of advantages for treating respiratory diseases that include targeting high doses directly to the lungs and reducing exposure of other organs to the medication, which improve effectiveness and minimize side effects. However, difficulties associated with aerosolized drug delivery to the lungs include drug losses in delivery devices and in the extrathoracic region of human upper airways. Intersubject variability of extrathoracic and thoracic drug deposition is a key issue as well and should be minimized. Improvements to respiratory drug delivery efficiency have been recently proposed by Dr. P. Worth Longest and Dr. Michael Hindle through the use controlled condensational growth methods, which include enhanced condensational growth (ECG) and excipient enhanced growth (EEG). These methods reduce inhaled drug loss through the introduction of an aerosol with an initial submicrometer aerodynamic diameter, which then experiences condensational growth to increase droplet size and enhance thoracic deposition. Tracheobronchial and nasal human airway computational models were developed for this study to assess drug delivery using conventional and EEG methods. Computational versions of these models are used to assess drug delivery and variability with computational fluid dynamics (CFD) simulations, which are validated with experimental data where possible. Using CFD, steady state delivery of albuterol sulfate (AS) during high flow therapy (HFT) through a nasal cannula was characterized with four nasal models developed for this study, with results indicating an increase in average delivered dose from 24.0% with a conventional method to 82.2% with the EEG technique and an initially sized 0.9 µm aerosol, with a corresponding decrease in the coefficient of variation from 15% to 3%. Transient CFD simulations of nebulized AS administration through a mask during noninvasive positive pressure ventilation (NPPV) were performed and validated with experimental data, which resulted in 40.5% delivered dose with the EEG method as compared with 19.5% for a conventional method and a common inhalation profile. Using two newly created face-nose-mouth-throat models, dry powder delivery of ciprofloxacin during NPPV was assessed for the first time with steady state CFD predictions, which showed an increase in average delivered lung dose through a new mask design of 78.2% for the EEG method as compared with 36.2% for conventional delivery, while corresponding differences in delivered dose between the two models were reduced from 45.4% to 12.8% with EEG. In conclusion, results of this study demonstrate (i) the use of highly realistic in silico and in vitro models to predict the lung delivery of inhaled pharmaceutical aerosols, (ii) indicate that the EEG approach can reduce variability in nose-to-lung aerosol delivery through a nasal cannula by a factor of five, and (iii) introduce new high efficiency methods for administering aerosols during NPPV, which represents an area of current clinical need

Heparan sulphate inhibition of cell proliferation induced by TGFβ and PDGF

The effect of glycosaminoglycans (GAGs) on the proliferation of smooth muscle cells (SMC) and fibroblasts was assessed by culturing cells with or without GAGs. Porcine heparan sulphate (HS) inhibited proliferation in a dose dependent manner. At 167 μg/ml of HS this reached 88% and 72% inhibition of SMC and fibroblast growth, respectively. Pig and beef mucosal heparins also blocked proliferation, but to a lesser extent. In contrast, beef lung heparin, chondroitin sulphate, and dermatan sulphate failed to block growth factor induced proliferation. Continuous presence of HS was not required, suggesting that the inhibitory effects resulted from a direct effect on the cell rather than an interaction of the GAG with growth factors. The mechanism by which GAGs inhibit proliferation will be addressed in future studies

Recovery of Streptococcus mutans and Streptococcus sanguis from a dental explorer after clinical examination of single human teeth

Certain aspects of the bacterial flora adhering to a dental explorer following a tactile diagnostic examination of a single tooth were investigated. Plaque present on the explorer was dislodged, and suspended into a reduced transport fluid by sonification. After serial dilution, suitable aliquots were placed on a high sucrose-containing medium, and on a mannitol medium. Colonies resembling Streptococcus mutans and Streptococcus sanguis were enumerated on these media. The explorer removed approximately 3-7 x 106 bacteria from a single tooth. Streptococcus mutans accounted for 17 per cent of the isolates from carious teeth and for 1.6 per cent of the isolates found on noncarious teeth. This difference was significant at the p Strep. sanguis were significantly higher in material removed from noncarious teeth than in plaque removed from the carious teeth.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/33912/1/0000177.pd

The unresolved safety concerns of bovine thrombin

A recent review has suggested that bovine thrombin is not associated with an increased risk of bleeding in surgical populations. In spite of extremely limited evidence available, many valuable resources (e.g. safety surveillance and post-marketing programs, case reports) were excluded in reaching this conclusion. While waiting for the adequately powered, controlled clinical trials to address the effects of bovine thrombin on bleeding and thrombotic events, the potential risk cannot be simply ignored. Rather, continued vigilance in the post-surgical setting for bleeding events that may be associated with the development of acquired coagulation factor inhibitors following bovine thrombin administration is warranted

IgG-class anti-PF4/heparin antibodies and symptomatic DVT in orthopedic surgery patients receiving different anti-thromboembolic prophylaxis therapeutics

<p>Abstract</p> <p>Background</p> <p>Heparin-induced thrombocytopenia (HIT) is a thromboembolic complication that can occur with unfractionated heparin (UFH) or low molecular weight heparin (LMWH). Our objective was to determine and compare the incidence of IgG-class HIT antibodies in patients undergoing total hip arthroplasty (THA) or total knee arthroplasty (TKA) with different antithrombotic prophylaxis therapies and their contributions to the occurrence of venous thromboembolism (VTE).</p> <p>Methods</p> <p>A prospective observational study was performed for 374 Japanese patients undergoing THA or TKA to determine the incidence of VTE. IgG-class anti-PF4/heparin antibodies were measured using IgG-specific EIA before and after the operation.</p> <p>Results</p> <p>In the clinical outcome, the incidence of symptomatic deep vein thrombosis (DVT) was 15.0% (56/374, TKA; 35, THA; 21) and pulmonary emboli (PE) were not observed. The total seroconversion incidence of IgG-class PF4/heparin antibodies was 19.8% (74/374). The seroconversion incidence of IgG-class PF4/heparin antibodies was higher in patients receiving UFH (32.7%) compared to those receiving LMWH (9.5%) or fondaparinux (14.8%). Furthermore, the seroconversion incidence was significantly higher in patients undergoing TKA compared to those undergoing THA. Based on multivariate analysis, seroconversion of the IgG-class PF4/heparin antibodies was independent a risk factor for symptomatic DVT.</p> <p>Conclusion</p> <p>Our findings show that the seroconversion of IgG-class anti-PF4/heparin antibodies differed with various anti-thrombotic prophylaxis therapeutics and was associated with the risk of DVT in a subset of patients undergoing total joint arthroplasty (TKA and THA).</p

Entry of Human Papillomavirus Type 16 by Actin-Dependent, Clathrin- and Lipid Raft-Independent Endocytosis

Infectious endocytosis of incoming human papillomavirus type 16 (HPV-16), the main etiological agent of cervical cancer, is poorly characterized in terms of cellular requirements and pathways. Conflicting reports attribute HPV-16 entry to clathrin-dependent and -independent mechanisms. To comprehensively describe the cell biological features of HPV-16 entry into human epithelial cells, we compared HPV-16 pseudovirion (PsV) infection in the context of cell perturbations (drug inhibition, siRNA silencing, overexpression of dominant mutants) to five other viruses (influenza A virus, Semliki Forest virus, simian virus 40, vesicular stomatitis virus, and vaccinia virus) with defined endocytic requirements. Our analysis included infection data, i.e. GFP expression after plasmid delivery by HPV-16 PsV, and endocytosis assays in combination with electron, immunofluorescence, and video microscopy. The results indicated that HPV-16 entry into HeLa and HaCaT cells was clathrin-, caveolin-, cholesterol- and dynamin-independent. The virus made use of a potentially novel ligand-induced endocytic pathway related to macropinocytosis. This pathway was distinct from classical macropinocytosis in regards to vesicle size, cholesterol-sensitivity, and GTPase requirements, but similar in respect to the need for tyrosine kinase signaling, actin dynamics, Na+/H+ exchangers, PAK-1 and PKC. After internalization the virus was transported to late endosomes and/or endolysosomes, and activated through exposure to low pH

Old and new oral anticoagulants : food, herbal medicines and drug interactions

The most commonly prescribed oral anticoagulants worldwide are the vitamin K antagonists (VKAs) such as warfarin. Factors affecting the pharmacokinetics of VKAs are important because deviations from their narrow therapeutic window can result in bleedings due to over-anticoagulation or thrombosis because of under-anticoagulation. In addition to pharmacodynamic interactions (e.g., augmented bleeding risk for concomitant use of NSAIDs), interactions with drugs, foods, herbs, and over-the-counter medications may affect the risk/benefit ratio of VKAs. Direct oral anticoagulants (DOACs) including Factor Xa inhibitors (rivaroxaban, apixaban and edoxaban) and thrombin inhibitor (dabigatran) are poised to replace warfarin. Phase-3 studies and real-world evaluations have established that the safety profile of DOACs is superior to those of VKAs. However, some pharmacokinetic and pharmacodynamic interactions are expected. Herein we present a critical review of VKAs and DOACs with focus on their potential for interactions with drugs, foods, herbs and over-the-counter medications