Microneedle devices have been proposed as a minimally invasive delivery system for the intradermal administration of nucleic acids, both plasmid DNA (pDNA) and siRNA, to treat localised disease or ...provide vaccination. Different microneedle types and application methods have been investigated in the laboratory, but limited and irreproducible levels of gene expression have proven to be significant challenges to pre-clinical to clinical progression. This study is the first to explore the potential of a hollow microneedle device for the delivery and subsequent expression of pDNA in human skin. The regulatory approved MicronJet600® (MicronJet hereafter) device was used to deliver reporter plasmids (pCMVβ and pEGFP-N1) into viable excised human skin. Exogenous gene expression was subsequently detected at multiple locations that were distant from the injection site but within the confines of the bleb created by the intradermal bolus. The observed levels of gene expression in the tissue are at least comparable to that achieved by the most invasive microneedle application methods e.g. lateral application of a microneedle. Gene expression was predominantly located in the epidermis, although also evident in the papillary dermis. Optical coherence tomography permitted real time visualisation of the sub-surface skin architecture and, unlike a conventional intradermal injection, MicronJet administration of a 50μL bolus appears to create multiple superficial microdisruptions in the papillary dermis and epidermis. These were co-localised with expression of the pCMVβ reporter plasmid. We have therefore shown, for the first time, that a hollow microneedle device can facilitate efficient and reproducible gene expression of exogenous naked pDNA in human skin using volumes that are considered to be standard for intradermal administration, and postulate a hydrodynamic effect as the mechanism of gene delivery.
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Digital volume correlation (DVC), the three-dimensional (3D) extension of digital image correlation (DIC), measures internal 3D material displacement fields by correlating intensity patterns within ...interrogation windows. In recent years DVC algorithms have gained increased attention in experimental mechanics, material science, and biomechanics. In particular, the application of DVC algorithms to quantify cell-induced material deformations has generated a demand for user-friendly, and computationally efficient DVC approaches capable of detecting large, non-linear deformation fields. We address these challenges by presenting a fast iterative digital volume correlation method (FIDVC), which can be run on a personal computer with computation times on the order of 1–2 min. The FIDVC algorithm employs a unique deformation-warping scheme capable of capturing any general non-linear finite deformation. The validation of the FIDVC algorithm shows that our technique provides a unique, fast and effective experimental approach for measuring non-linear 3D deformations with high spatial resolution.
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Antigen specific immunotherapy aims to tolerise patients to specific autoantigens that are responsible for the pathology of an autoimmune disease. Immune tolerance is generated in ...conditions where the immune response is suppressed and thus gold nanoparticles (AuNPs) are an attractive drug delivery platform due to their anti-inflammatory effects and their potential to facilitate temporal and spatial delivery of a peptide autoantigen in conjunction with pro-tolerogenic elements. In this study we have covalently attached an autoantigen, currently under clinical evaluation for the treatment of type 1 diabetes (PIC19-A3 peptide), to AuNPs to create nanoscale (<5 nm), negatively charged (−40 to −60 mV) AuNP-peptide complexes for immunotherapy. We also employ a clinically approved microneedle delivery system, MicronJet600, to facilitate minimally-invasive intradermal delivery of the nanoparticle constructs to target skin-resident antigen presenting cells, which are known to be apposite target cells for immunotherapy. The AuNP-peptide complexes remain physically stable upon extrusion through microneedles and when delivered into ex vivo human skin they are able to diffuse rapidly and widely throughout the dermis (their site of deposition) and, perhaps more surprisingly, the overlying epidermal layer. Intracellular uptake was extensive, with Langerhans cells proving to be the most efficient cells at internalising the AuNP-peptide complex (94% of the local population within the treated region of skin). In vitro studies showed that uptake of the AuNP-peptide complexes by dendritic cells reduced the capacity of these cells to activate naïve T cells. This indicator of biological functionality encourages further development of the AuNP-peptide formulation, which is now being evaluated in clinical trials.
Abstract
Antigen-specific immunotherapy is an immunomodulatory strategy for autoimmune diseases, such as type 1 diabetes, in which patients are treated with autoantigens to promote immune tolerance, ...stop autoimmune β-cell destruction and prevent permanent dependence on exogenous insulin. In this study, human proinsulin peptide C19-A3 (known for its positive safety profile) was conjugated to ultrasmall gold nanoparticles (GNPs), an attractive drug delivery platform due to the potential anti-inflammatory properties of gold. We hypothesised that microneedle intradermal delivery of C19-A3 GNP may improve peptide pharmacokinetics and induce tolerogenic immunomodulation and proceeded to evaluate its safety and feasibility in a first-in-human trial. Allowing for the limitation of the small number of participants, intradermal administration of C19-A3 GNP appears safe and well tolerated in participants with type 1 diabetes. The associated prolonged skin retention of C19-A3 GNP after intradermal administration offers a number of possibilities to enhance its tolerogenic potential, which should be explored in future studies
The normal fasting plasma glucose level was recently defined as less than 100 mg per deciliter (5.55 mmol per liter). Whether higher fasting plasma glucose levels within this range independently ...predict type 2 diabetes in young adults is unclear.
We obtained blood measurements, data from physical examinations, and medical and lifestyle information from men in the Israel Defense Forces who were 26 to 45 years of age.
A total of 208 incident cases of type 2 diabetes occurred during 74,309 person-years of follow-up (from 1992 through 2004) among 13,163 subjects who had baseline fasting plasma glucose levels of less than 100 mg per deciliter. A multivariate model, adjusted for age, family history of diabetes, body-mass index, physical-activity level, smoking status, and serum triglyceride levels, revealed a progressively increased risk of type 2 diabetes in men with fasting plasma glucose levels of 87 mg per deciliter (4.83 mmol per liter) or more, as compared with those whose levels were in the bottom quintile (less than 81 mg per deciliter 4.5 mmol per liter, P for trend <0.001). In multivariate models, men with serum triglyceride levels of 150 mg per deciliter (1.69 mmol per liter) or more, combined with fasting plasma glucose levels of 91 to 99 mg per deciliter (5.05 to 5.50 mmol per liter), had a hazard ratio of 8.23 (95 percent confidence interval, 3.6 to 19.0) for diabetes, as compared with men with a combined triglyceride level of less than 150 mg per deciliter and fasting glucose levels of less than 86 mg per deciliter (4.77 mmol per liter). The joint effect of a body-mass index (the weight in kilograms divided by the square of the height in meters) of 30 or more and a fasting plasma glucose level of 91 to 99 mg per deciliter resulted in a hazard ratio of 8.29 (95 percent confidence interval, 3.8 to 17.8), as compared with a body-mass index of less than 25 and a fasting plasma glucose level of less than 86 mg per deciliter.
Higher fasting plasma glucose levels within the normoglycemic range constitute an independent risk factor for type 2 diabetes among young men, and such levels may help, along with body-mass index and triglyceride levels, to identify apparently healthy men at increased risk for diabetes.
Live-attenuated oral rotavirus (RV) vaccines have lower efficacy in low income countries, and additionally are associated with a rare but severe adverse event, intussusception. We have been pursuing ...the development of an inactivated rotavirus vaccine (IRV) using the human rotavirus strain CDC-9 (G1P8) through parenteral immunization and previously demonstrated dose sparing and enhanced immunogenicity of intradermal (ID) unadjuvanted IRV using a coated microneedle patch in comparison with intramuscular (IM) administration in mice. The aim of this study was to evaluate the immune response and protection against RV infection and diarrhea conferred by the administration of the ID unadjuvanted IRV using the microneedle device MicronJet600® in neonatal gnotobiotic (Gn) piglets challenged with virulent Wa G1P8 human RV. Three doses of 5 μg IRV when administered intradermally and 5 μg IRV formulated with aluminum hydroxide Al(OH)3 when administered intramuscularly induced comparable rotavirus-specific antibody titers of IgA, IgG, IgG avidity index and neutralizing activity in sera of neonatal piglets. Both IRV vaccination regimens protected against RV antigen shedding in stools, and reduced the cumulative diarrhea scores in the piglets. This study demonstrated that the ID and IM administrations of IRV are immunogenic and protective against RV-induced diarrhea in neonatal piglets. Our findings highlight the potential value of an adjuvant sparing effect of the IRV ID delivery route.
Several basic properties of pond bottom soil are shown to be related, a relation that enable to evaluate pond bottom soil characteristics through the determination of one parameter (e.g. soil ...moisture). In addition, these relationships give some insight into the properties of flooded sediments. Unlike terrestrial soils, made of gas, liquid and solid phases, flooded sediments are made practically of only two phases, liquid and solid. Since all voids are filled with water, it is possible to evaluate soil porosity and bulk density, directly from the moisture content of the soil, a property easily determined. The correlation between bulk density and organic matter was tested in six different systems (
n=868), including rivers and fish pond sediments in Israel, fish pond sediments in Alabama, USA, and Abbassa, Egypt, lake sediments in New Zealand, alpine lake sediments in Colorado, USA, and sea floor sediments from the Northwest African continental slope. Sediment bulk density was inversely related to the organic carbon concentration. The regression for all the data points was:
Bulk density (
g/cm
3)=1.776−0.363
Log
e
OC
(R
2=0.70)
where OC is the organic carbon concentration (mg/g). The relationship between sediment moisture, bulk density and organic carbon described here can be used as a simple means to estimate the organic content and bulk density of flooded mineral soils by a simple determination of a sediment water content.
A report of seven people who accidentally drank a juice contaminated with CS (o-chlorobenzylidene malononitrile) is given. Due to its mucosal irritating properties, CS (also known as "tear gas") is ...commonly used by policemen and soldiers in riot control. However, only a few reports of its ingestion by humans exist. Ingestion of CS may cause immediate irritation of the oral mucosa and gastrointestinal symptoms later on. Damage of internal organs, which has been shown in animals but only rarely in humans, is probably related to the dose ingested. The extensive use of CS gas merits recognition of the signs and symptoms of its exposure in order to reduce anxiety in both patients and medical staff and to facilitate fast and efficient management.
Smoking habits and obesity in young adults Zimlichman, Eyal; Kochba, Ilan; Mimouni, Francis B. ...
Addiction (Abingdon, England),
July 2005, Letnik:
100, Številka:
7
Journal Article
Recenzirano
ABSTRACT
Aims The aim of this work was to study the association between obesity and smoking habits in young adults. Specifically, we tested the hypothesis that obesity does not prevent young adults ...from smoking and conversely smoking does not protect against obesity.
Design and setting Trained nurses interviewed participants concerning demographic data and health behaviors such as smoking. At the time of the interview, weight and height were measured. Data were analyzed retrospectively.
Participants A representative sample of Israel Defense Force (IDF) personnel upon discharge from compulsory service, usually at the age of 20–21 years.
Findings Overall, 29 745 participants were included during the 13‐year study (16 363 males and 13 382 females). Smoking rates were higher among obese participants than among overweight and non‐obese participants (34.9%, 37.1%, 43.6% for non‐obese, overweight and obese, respectively; P < 0.001). Mean number of cigarettes smoked per day were also higher among smokers that were obese and overweight compared to the non‐obese (15.2 ± 9.2, 15.6 ± 10.7, 18.0 ± 9.8, respectively; P < 0.001). Overweight and obesity were associated with the father's lower academic educational level. In logistic regression analysis, obesity, year of study and parental academic education were correlated independently with smoking (P < 0.001).
Conclusion The positive association between obesity and smoking suggests that obesity is not a deterrent to smoking and also that smoking does not help to prevent obesity.
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