Insulin Depot Formation in Subcutaneous Tissue

Background

The size and geometry of an insulin depot that is formed during subcutaneous administration by an insulin pump is evaluated. A novel method is used to visualize accurately the depot formation for small volumes of insulin (of the order of 10–100 µl) at a given point in time. Conventional visualization methods such as magnetic resonance imaging are unable to provide such accurate measurements because of their coarse imaging resolution and long measurement time.

Methods

The described method consists of subcutaneously infusing dyed insulin into porcine tissue and subsequently shock freezing it with liquid nitrogen. The frozen sample is then sliced into thin layers using a cryomicrotome. A digital image of each layer is taken and then processed with proprietary software, which identifies the dyed areas on each layer and reconstructs a three-dimensional model of the insulin depot with a planar resolution of 30 × 30 µm² and a depth resolution of 100 µm. Since this process is not viable for living organisms, porcine tissue was used immediately following slaughter of the animal.

Results

To date, it is most often assumed that the insulin depot takes the shape of a sphere around the tip of the cannula (e.g., 50 µl insulin equates to a spherical radius of 2.3 mm). However, in practice, such a depot form is never observed. Instead, the insulin depot initially spreads laterally (i.e., parallel) to the skin surface and in the collagen matrix that binds the adipose cells together. The depot outreach increases with larger infused volumes, e.g., maximum outreach measured at 5.0/5.7/7.1 mm (quartiles, n = 17) for 50 µl of infused insulin. Beyond a given infused volume (approximately 100 µl), the insulin also starts to spread perpendicular to the skin surface.

Conclusions

It is concluded that formation of the insulin depot depends on the opening of channels at the boundaries between adipose cells. Hence the insulin follows a path of least resistance and depot formation is determined by the local structure of the subcutaneous tissue.     

Biomechanical strength dependence on mammalian airway length

BackgroundThe trachea is the uppermost respiratory airway element connecting the larynx to the bronchi Airway reconstructions in humans are often developed from animal models but there is limited knowledge comparing tracheal biomechanics between species. We aimed to assess the structure and biomechanics of porcine, canine, caprine and human airways.MethodsTracheas from pigs (n=15), goats (n=9) and canines (n=9) were divided into three groups (4, 6 and 8-ringswhile human left principal brochi (n=12) were divided into two groups (3and-rings). Airway structures were compared using histology and scanning electron microscopy. Biomechanical properties were measured subjecting samples to uniaxial tension and compression, recording the elastic modulus and (tensile and compressive) strengths.ResultsThe structures of animal tracheal and human bronchia appeared similar. Biomechanical testing revealed that the elastic modulus of 8-ring tracheas was 1,190.48±363.68, 2,572.00±608.19 and 1,771.27±145.54 kPa, for porcine, canine and caprine samples, respectively, while corresponding tensile strengths were 437.63±191.41, 808.38±223.48 and 445.76±44.00 kPa. Comparable measures of anterior-posterior (A-P) compression strengths were 7.94±0.82, 7.54±0.07 and 8.10±1.87 N, respectively, whereas lateral compression strengths were 8.75±0.82, 14.55±2.29 and 11.12±0.40 N. Compression testing of human samples showed significant differences (P<0.05) between the 3-ring (A-P, 1.06±0.02 N; lateral, 0.55±0.06 N) and 5-ring groups (A-P, 1.08±0.64 N; lateral, 2.32±1.95 N).ConclusionsThe tensile and compressive strengths of mammalian airways show positive correlations with the cartilage ring number (length). On the basis of structural and biomechanical comparisons, porcine, canine and caprine species appear suitable models for the study of airway reconstruction in human.     

Blue Light-Activated Riboflavin Phosphate Promotes Collagen Crosslinking to Modify the Properties of Connective Tissues

Reduced amounts of collagen and fragmented collagen fibers are characteristics of aging skin. Recently, user-friendly, at-home personal aesthetic devices using light-emitting diode (LED) light have been used for cost-effective and safe skin improvement. However, to dramatically improve the skin via collagen repair, we need to develop an LED-responsive photosensitizer. Corneal collagen crosslinking uses ultraviolet light to activate riboflavin phosphate (RFP) and is used in ophthalmology. RFP is a biocompatible photosensitizer derived from vitamin B₂. This study aimed to prove that RFP combined with blue light (BL) can increase collagen crosslinking density, improving its mechanical properties in skin tissue and enhancing skin elasticity. We confirmed the RFP-induced photo-crosslinking in pure collagen by studying changes in its dynamic modulus and matrix morphology using collagen hydrogels. We also measured the changes in the mechanical properties after applying photo-crosslinking on porcine skin. The Young’s modulus (1.07 ± 0.12 MPa) and tensile strength (11.04 ± 1.06 MPa) of the porcine skin after photo-crosslinking were 2.8 and 3.5 times better compared to those of normal porcine skin, respectively. Thus, photo-crosslinking through RFP and BL irradiation can be potentially used for skin improvement using aesthetic LED devices.     

Differential diagnosis of benign and malignant branch duct intraductal papillary mucinous neoplasm using contrast-enhanced endoscopic ultrasonography

AIM: To elucidate the role of contrast-enhanced endoscopic ultrasonography (CE-EUS) in the diagnosis of branch duct intraductal papillary mucinous neoplasm (BD-IPMN).METHODS: A total of 50 patients diagnosed with BD-IPMN by computed tomography (CT) and endoscopic ultrasonography (EUS) at our institute were included in this study. CE-EUS was performed when mural lesions were detected by EUS. The diagnostic accuracy for identifying mural nodules (MNs) was evaluated by CT, EUS, and EUS combined with CE-EUS. In the patients who underwent resection, the accuracy of measuring MN height with each imaging modality was compared. The cut-off values to diagnose malignant BD-IPMNs based on MN height for each imaging modality were determined using receiver operating characteristic curve analysis.RESULTS: Fifteen patients were diagnosed with BD-IPMN with MNs and underwent resection. The remaining 35 patients were diagnosed with BD-IPMN without MNs and underwent follow-up monitoring. The pathological findings revealed 14 cases with MNs and one case without. The accuracy for diagnosing MNs was 92% using CT and 72% using EUS; the diagnostic accuracy increased to 98% when EUS and CE-EUS were combined. The accuracy for measuring MN height significantly improved when using CE-EUS compared with using CT or EUS (median measurement error value, CT: 3.3 mm vs CE-EUS: 0.6 mm, P < 0.05; EUS: 2.1 mm vs CE-EUS: 0.6 mm, P < 0.01). A cut-off value of 8.8 mm for MN height as measured by CE-EUS improved the accuracy of diagnosing malignant BD-IPMN to 93%.CONCLUSION: Using CE-EUS to measure MN height provides a highly accurate method for differentiating benign from malignant BD-IPMN.     

Assessment of the Effect of Structural Modification of Ibuprofen on the Penetration of Ibuprofen from Pentravan® (Semisolid) Formulation Using Human Skin and a Transdermal Diffusion Test Model

The effect of transdermal vehicle (Pentravan^®) on skin permeability was examined for unmodified ibuprofen (IBU) and ion pairs of ibuprofen with new L-valine alkyl esters [ValOR][IBU]. The percutaneous permeation across the human skin and transdermal diffusion test model (Strat-M^® membranes) of ibuprofen and its structural modification were measured and compared using Franz diffusion cells. For comparison, the penetration of ibuprofen from a commercial product was also investigated. The cumulative amount of drug permeated through human skin at the end of the 24 h study was highest for ibuprofen derivatives containing propyl (C3), isopropyl (C3), ethyl (C2), and butyl (C4) esters. For Strat-M^®, the best results were obtained with the alkyl chain length of the ester from C2 to C5. The permeation profiles and parameters were appointed, such as steady-state flux, lag time, and permeability coefficient. It has been shown that L-valine alkyl ester ibuprofenates, with the propyl, butyl, and amyl chain, exhibit a higher permeation rate than ibuprofen. The diffusion parameters of analyzed drugs through human skin and Strat-M^® were similar and with good correlation. The resulting Pentravan-based creams with ibuprofen in the form of an ionic pair represent a potential alternative to other forms of the drug-containing analgesics administered transdermally. Furthermore, the Strat-M^® membranes can be used to assess the permeation of transdermal preparations containing anti-inflammatory drugs.     

Graphene Oxide Topical Administration: Skin Permeability Studies

Nanostructured carriers have been widely used in pharmaceutical formulations for dermatological treatment. They offer targeted drug delivery, sustained release, improved biostability, and low toxicity, usually presenting advantages over conventional formulations. Due to its large surface area, small size and photothermal properties, graphene oxide (GO) has the potential to be used for such applications. Nanographene oxide (GOn) presented average sizes of 197.6 ± 11.8 nm, and a surface charge of −39.4 ± 1.8 mV, being stable in water for over 6 months. 55.5% of the mass of GOn dispersion (at a concentration of 1000 µg mL⁻¹) permeated the skin after 6 h of exposure. GOn dispersions have been shown to absorb near-infrared radiation, reaching temperatures up to 45.7 °C, within mild the photothermal therapy temperature range. Furthermore, GOn in amounts superior to those which could permeate the skin were shown not to affect human skin fibroblasts (HFF-1) morphology or viability, after 24 h of incubation. Due to its large size, no skin permeation was observed for graphite particles in aqueous dispersions stabilized with Pluronic P-123 (Gt–P-123). Altogether, for the first time, Gon’s potential as a topic administration agent and for delivery of photothermal therapy has been demonstrated.     

Preliminary Evaluation of a New Semi-Closed-Loop Insulin Therapy System Over the Prandial Period in Adult Patients With Type 1 Diabetes: The WP6.0 Diabeloop Study

There is room for improvement in the algorithms used in closed-loop insulin therapy during the prandial period. This pilot study evaluated the efficacy and safety of the Diabeloop algorithm (model predictive control type) during the postprandial period. This 2-center clinical trial compared interstitial glucose levels over two 5-hour periods (with/without the algorithm) following a calibrated lunch. On the control day, the amount of insulin delivered by the pump was determined according to the patient’s usual parameters. On the test day, 50% or 75% of the theoretical bolus required was delivered, while the algorithm, informed of carbohydrate intake, proposed changes to insulin delivery every 15 minutes using modeling to forecast glucose levels. The primary endpoint was percentage of time spent at near normoglycemia (70-180 mg/dl). Twelve patients with type 1 diabetes (9 men, age 35.6 ± 12.7 years, HbA1c 7.3 ± 0.8%) were included. The percentage of time spent in the target range was 84.5 ± 20.8 (test day) versus 69.2 ± 33.9% (control day, P = .11). The percentage of time spent in hypoglycemia < 70 mg/dl was 0.2 ± 0.8 (test) versus 4.4 ± 8.2% (control, P = .18). Interstitial glucose at the end of the test (5 hours) was 127.5 ± 40.1 (test) versus 146 ± 53.5 mg/dl (control, P = .25). The insulin doses did not differ, and no differences were observed between the 50% and 75% boluses. In a semi-closed-loop configuration with manual priming boluses (25% or 50% reduction), the Diabeloop v1 algorithm was as successful as the manual method in determining the prandial bolus, without any exposure to excessive hypoglycemic risk.     

Base Materials’ Influence on Fracture Resistance of Molars with MOD Cavities

The aim of this study was to compare fracture resistance of teeth presenting medium-sized mesial-occlusal-distal (MOD) cavities using different base materials. Thirty-six extracted molars were immersed for 48 h in saline solution (0.1% thymol at 4 °C) and divided into six groups. In group A, the molars were untouched, and in group B, cavities were prepared, but not filled. In group C, we used zinc polycarboxylate cement, in group D—conventional glass ionomer cement, in group E—resin modified glass ionomer cement, and in group F—flow composite. Fracture resistance was tested using a universal loading machine (Lloyd Instruments) with a maximum force of 5 kN and a crosshead speed of 1.0 mm/min; we used NEXYGEN Data Analysis Software and ANOVA Method (p < 0.05). The smallest load that determined the sample failure was 2780 N for Group A, 865 N for Group B, 1210 N for Group C, 1340 N for Group D, 1630 N for Group E and 1742 N for Group F. The highest loads were 3050 N (A), 1040 N (B), 1430 N (C), 1500 N (D), 1790 N (E), and 3320 N (F), the mean values being 2902 ± 114 N (A), 972 ± 65 N (B), 1339 ± 84 N (C), 1415 ± 67 N (D), 1712 ± 62 N (E), and 2334 ± 662 N (F). A p = 0.000195 shows a statistically significant difference between groups C, D, E and F. For medium sized mesial-occlusal-distal (MOD) cavities, the best base material regarding fracture resistance was flow composite, followed by glass ionomer modified with resin, conventional glass ionomer cement and zinc polycarboxylate cement. It can be concluded that light-cured base materials are a better option for the analyzed use case, one of the possible reasons being their compatibility with the final restoration material, also light-cured.     

A Novel Alveolar Distractor Incorporating Nickel–Titanium Alloy Springs: A Preliminary In Vitro Study

A new design of an alveolar distractor using nickel–titanium (NiTi) open-coil springs was developed and investigated to produce distraction forces against the tensile forces of porcine attached gingiva to simulate human gingiva. We subjected 15 mm long NiTi open-coil springs (Highland and ORMCO) with three levels of forces (light, medium and heavy) to mechanical testing in a 37 ± 1 °C water bath. Ten strips of porcine mandibular attached gingiva were subjected to tensile tests to determine the resistance force. The forces from the springs were compared with the tensile forces from the porcine attached gingiva. Data between groups were analyzed with independent-samples T-tests (p-value < 0.05). The tensile strength and the Young modulus were greater in buccal compared to lingual porcine attached gingiva. Compared to other spring dimensions and companies, forces generated from 0.014 × 0.036″ ORMCO springs were the highest and could overcome the tensile resistance from porcine attached gingiva over the longest distraction range of 1.6 mm. This preliminary in vitro study introduced a new design of an alveolar distractor incorporated with NiTi open-coil springs that could generate light and continuous forces to overcome the resistance from porcine attached gingiva.     

A comparative study between computed tomography and endoscopic ultrasound in the detection of a mural nodule in intraductal papillary mucinous neoplasm –Multicenter observational study in Japan

Background/objectivesThe detection of malignancy is a major concern in the management of intraductal papillary mucinous neoplasm (IPMN). The height of the mural nodule (MN), estimated using endoscopic ultrasound (EUS) and computed tomography (CT), has been considered crucial for predicting malignant IPMN. Currently, whether surveillance using CT or EUS alone is sufficient for detecting MNs remains unclear. This study aimed to compare the ability of CT and EUS to detect MNs in IPMN.MethodsThis multicenter, retrospective observational study was conducted in 11 Japanese tertiary institutions. Patients who underwent surgical resection of IPMN with MN after CT and EUS examinations were eligible to participate. The MN detection rates between CT and EUS were examined.ResultsTwo-hundred-and-forty patients who underwent preoperative EUS and CT had pathologically confirmed MNs. The MN detection rates of EUS and CT were 83% and 53%, respectively (p < 0.001). Additionally, the MN detection rate of EUS was significantly higher than that of CT regardless of morphological type (76% vs. 47% in branch-duct-type IPMN; 90% vs. 54% in mixed IPMN; 98% vs. 56% in main-duct-type IPMN; p < 0.001). Further, pathologically confirmed MNs ≥5 mm were more frequently observed on EUS than on CT (95% vs. 76%, p < 0.001).ConclusionsEUS was superior to CT for the detection of MN in IPMN. EUS surveillance is essential for the detection of MNs.     

Comparison of the fixation ability of headless compression screws and locking plate for metacarpal shaft transverse fracture

Metacarpal shaft fractures are common hand fractures. Although bone plates possess strong fixation ability, they have several limitations. The use of headless compression screws for fracture repair has been reported, but their fixation ability has not been understood clearly.This study aimed to compare the fixation ability of locked plate with that of headless compression screw for metacarpal fracture repair.A total of 14 artificial metacarpal bones (Sawbones, Vashon, WA, USA) were subjected to transverse metacarpal shaft fractures and divided into 2 groups. The first group of bones was fixed using locked plates (LP group), whereas the second group was fixed using headless compression screws (HC group). A material testing machine was used to perform cantilever bending tests, whereby maximum fracture force and stiffness were measured. The fixation methods were compared by conducting a Mann–Whitney U test.The maximum fracture force of the HC group (285.6 ± 57.3 N, median + interquartile range) was significantly higher than that of the LP group (227.8 ± 37.5 N; P < .05). The median of the HC group was 25.4% greater. However, no significant difference in stiffness (P > .05) was observed between the HC (65.2 ± 24.6 N/mm) and LP (61.7 ± 19.7 N/mm) groups.Headless compression screws exhibited greater fixability than did locked plates, particularly in its resistance to maximum fracture force.     

Generation of Monocyte-Derived Insulin-Producing Cells from Non-Human Primates According to an Optimized Protocol for the Generation ofPCMO-Derived Insulin-Producing Cells

Ob­jec­ti­ve: The vision of potential autologous cell therapy for the cure of diabetes encourages ongoing research. According to a previously published protocol for the generation of insulin-producing cells from human monocytes, we analyzed whether the addition of growth factors could increase insulin production. This protocol was then transferred to a non-human primate model by using either blood- or spleen-derived monocytes. Methods: Human monocytes were treated to dedifferentiate into programmable cells of monocytic origin (PCMO). In addition to the published protocol, PCMOs were then treated with either activin A, betacellulin, exendin 3 or 4. Cells were characterized by protein expression of insulin, Pdx-1, C-peptide and Glut-2. After identifying the optimal protocol, monocytes from baboon blood were isolated and the procedure was repeated. Spleen monocytes following splenectomy of a live baboon were differentiated and analyzed in the same manner and calculated in number and volume.Results: Insulin content of human cells was highest when cells were treated with activin A and their insulin content was 13 000 µU/1 million cells. Insulin-producing cells form primate monocytes could successfully be generated despite using human growth factors and serum. Expression of insulin, Pdx-1, C-peptide and Glut-2 was comparable to that of human neo-islets. Total insulin content of activin A-treated baboon monocytes was 16 000 µU/1 million cells.Conclusion: We were able to show that insulin-producing cells can be generated from baboon monocytes with human growth factors. The amount generated from one spleen could be enough to cure a baboon from experimentally induced diabetes in an autologous cell transplant setting.     

Single-cell mechanics provides a sensitive and quantitative means for probing amyloid-β peptide and neuronal cell interactions

By using a highly sensitive technique of atomic force microscopy-based single-cell compression, the rigidity of cultured N2a and HT22 neuronal cells was measured as a function of amyloid-β42 (Aβ42) protein treatment. Aβ42 oligomers led to significant cellular stiffening; for example, 90–360% higher force was required to reach 80% deformation for N2a cells. Disaggregated or fibrillar forms of Aβ42 showed much less change. These observations were explained by a combination of two factors: (i) incorporation of oligomer into cellular membrane, which resulted in an increase in the Young''s modulus of the membrane from 0.9 ± 0.4 to 1.85 ± 0.75 MPa for N2a cells and from 1.73 ± 0.90 to 5.5 ± 1.4 MPa for HT22 cells, and (ii) an increase in intracellular osmotic pressure (e.g., from 7 to 40 Pa for N2a cells) through unregulated ion influx. These findings and measurements provide a deeper, more characteristic, and quantitative insight into interactions between cells and Aβ42 oligomers, which have been considered the prime suspect for initiating neuronal dysfunction in Alzheimer''s disease.     

Medium-intensity,high-volume “hypertrophic” resistance training did not induce improvements in rapid force production in healthy older men

The aim of the study was to determine whether it is possible to improve both maximum and rapid force production using resistance training that is typically used to induce muscle hypertrophy in previously untrained older men. Subjects (60–72 years) performed 20 weeks of “hypertrophic” resistance training twice weekly (n = 27) or control (n = 11). Maximum dynamic and isometric leg press, as well as isometric force over 0–100 ms, and maximum concentric power tests were performed pre- and post-intervention. Muscle activity was assessed during these tests by surface electromyogram of the vastus lateralis and medialis muscles. Muscle hypertrophy was assessed by panoramic ultrasound of the vastus lateralis. The intervention group increased their maximum isometric (from 2268 ± 544 to 2538 ± 701 N) and dynamic force production (from 137 ± 24 to 165 ± 29 kg), and these changes were significantly different to control (isometric 12 ± 16 vs. 1 ± 9 %; dynamic 21 ± 12 vs. 2 ± 4 %). No within- or between-group differences were observed in rapid isometric force or concentric power. Relative increases in vastus lateralis cross-sectional area trended to be statistically greater in the intervention group (10 ± 8 vs. 3 ± 6 %, P = 0.061). It is recommendable that resistance training programs for older individuals integrate protocols emphasizing maximum force/muscle hypertrophy and rapid force production in order to induce comprehensive health-related and functionally important improvements in this population.     

Evaluation of Asymmetric Dimethylarginine (ADMA) Levels in Children with Growth Hormone Deficiency

Ob­jec­ti­ve: To investigate serum asymmetric dimethylarginine (ADMA) levels in children with isolated growth hormone deficiency (GHD) and to determine the effect of GH replacement therapy on these levels.Methods: 31 patients diagnosed with isolated GHD and 29 age-and sex-matched healthy children were enrolled in the study. Height, weight and waist circumference were measured in all subjects. Fasting serum insulin-like growth factor-1 (IGF-1), IGF binding protein-3, glucose, insulin and lipid levels were evaluated. Serum ADMA levels were assessed using the enzyme-linked immunosorbent assay technique. The same evaluations were repeated on the 3^rd and 6^th months of treatment in 28 of the GHD cases.Results: There were no significant differences in ADMA levels between the patient and control groups [0.513±0.130 (0.291-0.820) µmol/L vs. 0.573±0.199 (0.241-1.049) µmol/L]. There was a positive correlation between serum ADMA and HbA1c levels in the control group. In the GHD cases, ADMA levels negatively correlated with high-density lipoprotein levels and positively correlated with low-density lipoprotein levels. There was also a significant increase in ADMA levels in patients receiving GH therapy compared to pre-treatment levels [serum ADMA level, 1.075±0.133 (0.796-1.303) µmol/L at the 3rd month and 0.923±0.121 (0.695-1.159) µmol/L at the 6th month of treatment]. There was a negative correlation between ADMA levels and homeostasis model assessment of insulin resistance values at the 6th month evaluation. There were no relationships between ADMA levels and age, sex, or pubertal state either before or during the treatment.Conclusion: Serum ADMA levels were found to be similar in patients with GHD and in healthy children. However, serum ADMA levels showed a significant increase in GHD patients following GH replacement therapy.     

Permeability of Ibuprofen in the Form of Free Acid and Salts of L-Valine Alkyl Esters from a Hydrogel Formulation through Strat-M™ Membrane and Human Skin

This paper aimed to evaluate the effect of vehicle and chemical modifications of the structure of active compounds on the skin permeation and accumulation of ibuprofen [IBU]. In vitro permeation experiments were performed using human abdominal skin and Strat-M™ membrane. The HPLC method was used for quantitative determinations. The formulations tested were hydrogels containing IBU and its derivatives and commercial gel with ibuprofen. The results obtained indicate that Celugel^® had an enhancing effect on the skin penetration of IBU. The average cumulative mass of [IBU] after 24 h permeation test from Celugel^® formulation through human skin was over 3 times higher than for the commercial product. Three ibuprofen derivatives containing [ValOiPr][IBU], [ValOPr][IBU], and [ValOBu][IBU] cation were evaluated as chemical penetration enhancers. The cumulative mass after 24 h of penetration was 790.526 ± 41.426, 682.201 ± 29.910, and 684.538 ± 5.599 μg IBU cm⁻², respectively, compared to the formulation containing unmodified IBU-429.672 ± 60.151 μg IBU cm⁻². This study demonstrates the perspective of the transdermal hydrogel vehicle in conjunction with the modification of the drug as a potential faster drug delivery system.     

Immunization by vaccine-coated microneedle arrays protects against lethal influenza virus challenge

Influenza prophylaxis would benefit from a simple method to administer influenza vaccine into skin without the need for hypodermic needles. In this study, solid metal microneedle arrays (MNs) were investigated as a system for cutaneous vaccine delivery using influenza virus antigen. The MNs with 5 monument-shaped microneedles per array were produced and coated with inactivated influenza virus A/PR/8/34 (IIV). As much as 10 μg of viral proteins could be coated onto an array of 5 microneedles, and the coated IIV was delivered into skin at high efficiency within minutes. The coated MNs were used to immunize mice in comparison with conventional intramuscular injection at the same dose. Analysis of immune responses showed that a single immunization with IIV-coated MNs induced strong antibody responses against influenza virus, with significant levels of hemagglutination inhibition activities (>1:40), which were comparable to those induced by conventional intramuscular immunization. Moreover, mice immunized by a single dose of IIV coated on MNs were effectively protected against lethal challenge by a high dose of mouse-adapted influenza virus A/PR/8/34. These results show that MNs are highly effective as a simple method of vaccine delivery to elicit protective immune responses against virus infection.     

Evaluation of Intravascular Microdialysis for Continuous Blood Glucose Monitoring in Hypoglycemia: An Animal Model

Background:We have previously shown that intravascular microdialysis in a central vein is an accurate method for continuous glucose monitoring in patients undergoing cardiac surgery. However, no hypoglycemia occurred in our earlier studies, prompting further evaluation of the accuracy of intravascular microdialysis in the hypoglycemic range. Thus, this animal study was performed.Method:A porcine model was developed; hypoglycemia was induced using insulin injections. The pigs were monitored with intravascular microdialysis integrated in a triple-lumen central venous catheter. As reference, venous blood gas samples were taken every 5 minutes and analyzed in a blood gas analyzer. Ethical permission for the animal experiments was obtained from the Stockholm Regional Ethical Committee, reference no N397/09.Results:A total of 213 paired samples were obtained for analysis, and 126 (59.2%) of these were in the hypoglycemic range (<74 mg/dl). Using Clarke error grid analysis, 100% of the paired samples were in region AB and 99% in region A. The ISO standard (ISO15197) was met. Bland–Altman analysis showed bias (mean difference) ± limits of agreement was −0.18 ± 16.2 mg/dl. No influence from glucose infusions was seen. The microdialysis monitoring system was found to be very responsive in rapid changes in blood glucose concentration.Conclusions:This study shows that intravascular microdialysis in a central vein is an accurate method for continuous glucose monitoring in hypoglycemia in a porcine experimental model. Furthermore, the system was not influenced by glucose administration and was found to be responsive in rapid blood glucose fluctuations.     

Evaluation of the 3D Printing Accuracy of a Dental Model According to Its Internal Structure and Cross-Arch Plate Design: An In Vitro Study

The amount of photopolymer material consumed during the three-dimensional (3D) printing of a dental model varies with the volume and internal structure of the modeling data. This study analyzed how the internal structure and the presence of a cross-arch plate influence the accuracy of a 3D printed dental model. The model was designed with a U-shaped arch and the palate removed (Group U) or a cross-arch plate attached to the palate area (Group P), and the internal structure was divided into five types. The trueness and precision were analyzed for accuracy comparisons of the 3D printed models. Two-way ANOVA of the trueness revealed that the accuracy was 135.2 ± 26.3 µm (mean ± SD) in Group U and 85.6 ± 13.1 µm in Group P. Regarding the internal structure, the accuracy was 143.1 ± 46.8 µm in the 1.5 mm-thick shell group, which improved to 111.1 ± 31.9 µm and 106.7 ± 26.3 µm in the roughly filled and fully filled models, respectively. The precision was 70.3 ± 19.1 µm in Group U and 65.0 ± 8.8 µm in Group P. The results of this study suggest that a cross-arch plate is necessary for the accurate production of a model using 3D printing regardless of its internal structure. In Group U, the error during the printing process was higher for the hollowed models.     

Improved Insulin Absorption by Means of Standardized Injection Site Modulation Results in a Safer and More Efficient Prandial Insulin TreatmentA Review of the Existing Clinical Data

Temperature changes on the surface of the skin lead to modifications of subcutaneous microcirculation. This phenomenon is employed in a standardized way by the InsuPad device to stabilize skin conditions before injections, which is associated with enhanced prandial insulin absorption. Three programmed warming cycles to 40°C within 50 minutes are resulting in faster insulin appearance in the plasma. Early standardized meal tolerance studies indicated a substantial improvement in postprandial glucose control when the same short-acting insulin analog dose was applied using InsuPad, and a dose reduction by 20% resulted in comparable glucose excursions. Similar results were obtained when patients applied the device under real-world conditions for 1 month. The InsuPad device was also tested in a prospective, controlled, parallel 3-month real-world study with 145 well-controlled but insulin-resistant patients with type 1 or type 2 diabetes. Patients were treated to target in both treatment arms (6.2 ± 0.5% in each group), with or without the device. However, patients with InsuPad needed 28% less prandial insulin, needed 12.5% less total insulin, and had 46% less confirmed hypoglycemic events (blood glucose < 63 mg/dL) as compared to the control group. Except for very few inflammatory or allergic skin reactions, there were no device-specific adverse events reported from these studies. In conclusion, use of InsuPad when applying prandial insulin doses may result in a safer and more efficient treatment of type 1 or type 2 diabetes.