Fabrication of Eudragit polymeric nanoparticles using ultrasonic nebulization method for enhanced oral absorption of megestrol acetate.

Megestrol acetate (MGA) is used as a progestagen to treat advanced cancers in the breast or uterus and anorexia-cachexia syndrome in cancer patients. Due to its low solubility (BCS class II), MGA bioavailability needs to be enhanced for efficacy and safety. We developed MGA-encapsulated Eudragit® L100 (EUD) nanoparticles (MGA-EUD (1:1) and MGA-EUD (2:1)) using an ultrasonic nebulization method. MGA-EUD (1:1) and MGA-EUD (2:1) consisted of MGA and EUD at the mass ratios of 1:1 and 2:1. Their physicochemical properties, i.e. particle size, loading efficiency, morphology, and crystallinity were determined. Dissolution tests were performed using USP method II. For pharmacokinetics, they were orally administered at 50 mg/kg to mice. Microcrystalline MGA suspension (MGA-MC, Megace®, BMS) was used as control. MGA-EUD (1:1) and MGA-EUD (2:1) had a smooth and spherical shape of 0.70 and 1.05 µm in diameter with loading efficiencies of 93 and 95% showing amorphous states of MGA. They significantly enhanced the dissolution potential of MGA. Oral bioavailability of MGA-EUD (1:1) and MGA-EUD (2:1) increased 2.0- and 1.7-fold compared to that of MGA-MC. It suggests that ultrasonic nebulization method for the fabrication of polymeric nanoparticles is a promising approach to improve the bioavailability of poorly soluble drugs.

Abnormal changes in both mandibular salivary glands in a dog: Non-mineral radiopaque sialoliths.

A 10-year-old Maltese dog was presented with a firm mass on the left side of his neck. Physical examination confirmed a firm mass in the left and a submandibular swelling in the right cervical region. Sialolithiasis and associated sialocele in both mandibular salivary glands were suspected and bilateral sialoadenectomy was performed. The stones were identified as non-mineral sialoliths.

Changements anormaux dans les deux glandes salivaires mandibulaires chez un chien : sialolithes radiopaques non minéraux. Un chien Maltais âgé de 10 ans a été présenté avec une masse ferme du côté droit du cou. L'examen physique a confirmé une masse ferme dans l'enflure gauche et sous-mandibulaire dans la région cervicale droite. La sialolithiase et une sialocèle connexe dans les deux glandes salivaires mandibulaires ont été suspectées et une sialoadénectomie bilatérale a été réalisée. Les pierres ont été identifiées comme des sialolithes non minéraux.(Traduit par Isabelle Vallières).

Randomized controlled trial of digital therapeutics for temporomandibular disorder: A pilot study.

OBJECTIVES: Temporomandibular disorder (TMD) is a common condition that affects the temporomandibular joint (TMJ) and the muscles of the jaw, resulting in pain and dysfunction. TMD is affected by both behavioral and psychological factors. Digital therapeutics (DTx) can exert therapeutic effects by controlling behavioral factors through the delivery of appropriate interventions. Here, we report an open-label randomized control trial to evaluate the efficacy of DTx for TMD. METHODS: We recruited 40 participants diagnosed with TMD. Participants were randomly divided into an intervention group (DTx use, n = 20) and a control group (n = 20). The intervention group received the usual treatment process for TMD in addition to the use of the DTx. The control group received the usual treatments only. Patients in both groups were followed up for 3-4 weeks, and outcome data were collected and analyzed. RESULT: The intervention group showed a significant reduction in pain scores as measured by the numerical rating scale (NRS) (p = 0.016). Additionally, the intervention group showed a statistically significant increase in maximal mouth opening compared to the control group (p = 0.0079). However, there were no significant differences in improvement in the Jaw Functional Limitation Scale, Oral Behavior Checklist, and Patient Health Questionnaire-4 between the two groups (p = 0503, = 0.820, and = 0.943, respectively). CONCLUSION: This RCT reveals DTx potential in TMD, showing pain and mouth opening improvements with conventional treatment. But no significant changes were noted in other outcomes. The findings advocate for more extensive, long-term research to solidify DTx's role in TMD management. CLINICAL SIGNIFICANCE: This research underlines DTx potential to improve pain outcomes in TMD therapy, reinforcing its value as a complementary treatment modality.

Gait Pattern in Charcot-Marie-Tooth Disease Type 1A According to Disease Severity.

The aim of this study was to evaluate the characteristics of gait patterns in Charcot-Marie-Tooth disease type 1A (CMT1A) patients according to disease severity. Twenty-two CMT1A patients were enrolled and classified into two groups, according to the disease severity. The healthy control group consisted of 22 subjects with no gait impairment. Full barefoot three-dimensional gait analysis with temporospatial, kinematic, and kinetic data was performed among the mild and moderate CMT1A group and the control group. Minimal hip abduction, maximal hip extension generation, peak knee flexion moment at stance, ankle dorsiflexion at initial contact, maximal ankle plantarflexion at push-off and maximal ankle rotation moment at stance in the CMT1A group showed a significant difference compared to the control group (p < 0.05). In the moderate group, there were greater maximal hip flexion angles in swing, and smaller dorsiflexion angles at initial contact compared to the control group and mild group. CMT patients had typical gait characteristics and their gait patterns were different according to severity. The analysis of gait patterns in patients with CMT1A will help to understand gait function and provide important information for the treatment of patients with CMT in the future.

Effect of oestrus synchronisation through ovulation delay by vaccination against foot-and-mouth disease in Hanwoo (Bos taurus coreanae) cows.

BACKGROUND: In Korean cattle, after foot-and-mouth disease (FMD) vaccination, anovulation increases, acute immune response is stimulated. OBJECTIVE: Here, we aimed to improve the fertility rate by ovulation delay caused by the foot-and-mouth disease vaccine. METHODS: 160 cows (control, FMD, FMD+Gn250 and FMD+Gn500 groups, with 40 cows each) were used. We analysed the ovulation delay, ovulation rate, conception rate and acute-phase immune responses. RESULTS: In the group vaccinated only with FMD, the average follicle size was maintained at 12 mm and ovulation was delayed. The ovulation rate of the FMD+Gn500 group (500 µg gonadotropin-releasing hormone (GnRH) injections 3 days after the FMD vaccination) was the highest at 81.8%. The ovulation rate of the FMD+Gn250 group (250 µg GnRH injections 3 days after FMD vaccination) was 54.5%, and that of the control group (not FMD vaccinated) was 53.3%. The conception rate was 52.5% (19/40) in the control group, 37.5% (15/40) in the FMD+Gn250 group, and 67.5% (27/40) in the FMD+Gn500 group. Analysis of acute-phase immune response revealed that the plasma contents of haptoglobin and serum amyloid A increased up to 7 days after vaccination against FMD in all the experimental groups, except the control group. CONCLUSIONS: We concluded that ovulation delay can be employed to improve conception rate after FMD vaccination through a modified ovulation synchronisation method with GnRH.

Effect of Foot-and-Mouth Disease Vaccination on Acute Phase Immune Response and Anovulation in Hanwoo (Bos taurus coreanae).

Vaccination against foot-and-mouth disease is the most common method for preventing the spread of the disease; the negative effects include miscarriage, early embryo death, lower milk production, and decreased growth of fattening cattle. Therefore, in this study, we analyze the side effects of vaccination by determining the acute immune response and ovulation rate after vaccinating cows for foot-and-mouth disease. The test axis was synchronized with ovulation using 100 Hanwoo (Bos taurus coreanae) cows from the Gyeongsangbuk-do Livestock Research Institute; only individuals with estrus confirmed by ovarian ultrasound were used for the test. All test axes were artificially inseminated 21 days after the previous estrus date. The control group was administered 0.9% normal saline, the negative control was injected intramuscularly with lipopolysaccharide (LPS; 0.5 µg/kg), and the test group was administered a foot-and-mouth disease virus vaccine (FMDV vaccine; bioaftogen, O and A serotypes, inactivated vaccine) 2, 9, and 16 days before artificial insemination. White blood cells and neutrophils increased significantly 1 day after vaccination, and body temperature in the rumen increased for 16 h after vaccination. Ovulation was detected 1 day after artificial fertilization by ovarian ultrasound. The ovulation rates were as follows: control 89%, LPS 60%, FMDV vaccine (-2 d) 50%, FMDV vaccine (-9 d) 75%, and FMDV vaccine (-16 d) 75%. In particular, the FMDV vaccine (-2 d) test group confirmed that ovulation was delayed for 4 days after artificial insemination. In addition, it was confirmed that it took 9 days after inoculation for the plasma contents of haptoglobin and serum amyloid A to recover to the normal range as the main acute immune response factors. The conception rate of the FMDV vaccine (-2 d) group was 20%, which was significantly lower than that of the other test groups.

Increased Ruminoreticular Temperature and Body Activity after Foot-and-Mouth Vaccination in Pregnant Hanwoo (Bos taurus coreanae) Cows.

How does vaccination against foot-and-mouth disease (FMD) affect pregnant cows? Vaccination is the most effective method of preventing the spread of FMD, but it is linked to sporadic side effects, such as abortion and premature birth, which result in economic loss. In this study, ruminoreticular temperature and body activity were measured before and after FMD vaccination using a ruminoreticular biocapsule sensor in Hanwoo cows at different stages of pregnancy. Compared to the unvaccinated groups, the ruminoreticular temperature increased 12 h after vaccination in the vaccinated groups. This increase in temperature is significantly correlated to vaccination. Compared to the nonpregnant and early pregnancy groups, the ruminoreticular temperature of the late pregnancy group increased sharply by more than 40 °C. Moreover, in nonpregnant and early pregnancy groups, a rapid increase in body activity was observed after FMD vaccinations. Of the 73 pregnant vaccinated cows in the study, a total of five cases had side effects (four abortions and one premature birth). Therefore, changes in the ruminoreticular temperature and activity in pregnant cows can be used as raw data to further clarify the association of FMD vaccination with the loss of a fetus and possibly predict abortion, miscarriage, and premature birth following FMD vaccination.

Remodeling of Adhesion Network within Cancer Spheroids via Cell-Polymer Interaction.

3D spheroids are considered as the improved in vitro model to mimic the distinct arrangements of the cells in vivo. To date, low-attachment surfaces have been most widely used to induce the spontaneous aggregation of cells in suspension by simply tuning the relative strength of the cell-cell adhesion over cell-substrate adhesion. However, aggregating cancer cells into 3D clusters should mean more than just adjoining the cells in the physical proximity. The tumor cell functionality is strongly affected by the adhesion networks between cancer cells and extracellular matrix (ECM). Here, we performed an in-depth analysis of how the nonmetastatic breast cancer cells (MCF7) can be transformed to gain invasive phenotypes through compact aggregation into 3D spheroids on a functional polymer film surface, poly(2,4,6,8-tetravinyl-2,4,6,8-tetramethyl cyclotetrasiloxane) (pV4D4). By comparing the adhesion networks and invasion dynamics between 3D spheroids cultured on the pV4D4 surface with those cultured on conventional ultra-low-attachment (ULA) dishes, we report that only spheroids on the pV4D4 display active and sporadic cell-surface binding activities via dynamic protrusions, which correlates strongly with an increase in integrin ß1. Moreover, localized laminin expression at the core of the pV4D4-cultured spheroids confirms the prominence of the intimate integrin-laminin interactions prompted by the exposure to pV4D4. This study suggests that structurally and functionally dissimilar 3D spheroids can be generated from the same type of cells on the surfaces of different physicochemical properties without any chemical treatment or genetic manipulation.

Development of a Shape-Memory Tube to Prevent Vascular Stenosis.

Inserting a graft into vessels with different diameters frequently causes severe damage to the host vessels. Poor flow patency is an unresolved issue in grafts, particularly those with diameters less than 6 mm, because of vessel occlusion caused by disturbed blood flow following fast clotting. Herein, successful patency in the deployment of an ≈2 mm diameter graft into a porcine vessel is reported. A new library of property-tunable shape-memory polymers that prevent vessel damage by expanding the graft diameter circumferentially upon implantation is presented. The polymers undergo seven consecutive cycles of strain energy-preserved shape programming. Moreover, the new graft tube, which features a diffuser shape, minimizes disturbed flow formation and prevents thrombosis because its surface is coated with nitric-oxide-releasing peptides. Improved patency in a porcine vessel for 18 d is demonstrated while occlusive vascular remodeling occurs. These insights will help advance vascular graft design.

Comparison of marginal bone loss between internal- and external-connection dental implants in posterior areas without periodontal or peri-implant disease.

PURPOSE: The purpose of this retrospective study with 4-12 years of follow-up was to compare the marginal bone loss (MBL) between external-connection (EC) and internal-connection (IC) dental implants in posterior areas without periodontal or peri-implant disease on the adjacent teeth or implants. Additional factors influencing MBL were also evaluated. METHODS: This retrospective study was performed using dental records and radiographic data obtained from patients who had undergone dental implant treatment in the posterior area from March 2006 to March 2007. All the implants that were included had follow-up periods of more than 4 years after loading and satisfied the implant success criteria, without any peri-implant or periodontal disease on the adjacent implants or teeth. They were divided into 2 groups: EC and IC. Subgroup comparisons were conducted according to splinting and the use of cement in the restorations. A statistical analysis was performed using the Mann-Whitney U test for comparisons between 2 groups and the Kruskal-Wallis test for comparisons among more than 2 groups. RESULTS: A total of 355 implants in 170 patients (206 EC and 149 IC) fulfilled the inclusion criteria and were analyzed in this study. The mean MBL was 0.47 mm and 0.15 mm in the EC and IC implants, respectively, which was a statistically significant difference (P<0.001). Comparisons according to splinting (MBL of single implants: 0.34 mm, MBL of splinted implants: 0.31 mm, P=0.676) and cement use (MBL of cemented implants: 0.27 mm, MBL of non-cemented implants: 0.35 mm, P=0.178) showed no statistically significant differences in MBL, regardless of the implant connection type. CONCLUSIONS: IC implants showed a more favorable bone response regarding MBL in posterior areas without peri-implantitis or periodontal disease.

Transfer-molded wrappable microneedle meshes for perivascular drug delivery.

After surgical procedures such as coronary/peripheral bypass grafting or endarterectomy for the treatment of organ ischemia derived from atherosclerosis, intimal hyperplasia (IH) which leads to restenosis or occlusion at the site of graft anastomosis frequently occurs. In order to inhibit IH caused by abnormal growth of smooth muscle cells (SMCs) in tunica media, various perivascular drug delivery devices are reported for delivery of anti-proliferation drugs into vascular tissue. However, there still remain conflicting requirements such as local and unidirectional delivery vs device porosity, and conformal tight device installation vs pulsatile expansion and constriction of blood vessels. In this study, a biodegradable microneedle (MN) array is developed on a flexible woven surgical mesh using a transfer molding method. Mechanical properties of 'wrappable' MN meshes are investigated and compared to the properties of blood vessels. Ex vivo and in vivo animal studies demonstrate enhanced drug delivery efficiency, efficacy for IH reduction, and safety of MN mesh. In particular, MN mesh showed significantly reduced neointiamal formation (11.1%) compared to other competitive groups (23.7 and 22.2%) after 4-week in vivo animal study. Additionally, wrappable MN meshes effectively suppressed side effects such as IH due to mechanical constriction, loss of toxic drug to the surroundings, and cell death that were frequently observed with other previous perivascular drug delivery devices.

Evaluation of a canine small intestinal submucosal xenograft and polypropylene mesh as bioscaffolds in an abdominal full-thickness resection model of growing rats.

We evaluated the biological scaffold properties of canine small intestinal submucosa (SIS) compared to a those of polypropylene mesh in growing rats with full-thickness abdominal defects. SIS is used to repair musculoskeletal tissue while promoting cell migration and supporting tissue regeneration. Polypropylene mesh is a non-resorbable synthetic material that can endure mechanical tension. Canine SIS was obtained from donor German shepherds, and its porous collagen fiber structure was identified using scanning electron microscopy (SEM). A 2.50-cm(2) section of canine SIS (SIS group) or mesh (mesh group) was implanted in Sprague-Dawley rats. At 1, 2, 4, 12, and 24 weeks after surgery, the implants were histopathologically examined and tensile load was tested. One month after surgery, CD68+ macrophage numbers in the SIS group were increased, but the number of CD8+ T cells in this group declined more rapidly than that in rats treated with the mesh. In the SIS group, few adhesions and well-developed autologous abdominal muscle infiltration into the SIS collagen fibers were observed. No significant differences in the tensile load test results were found between the SIS and mesh groups at 24 weeks. Canine SIS may therefore be a suitable replacement for artificial biological scaffolds in small animals.

Use of canine small intestinal submucosa allograft for treating perineal hernias in two dogs.

Here, we describe two dogs in which canine small intestinal submucosa (SIS) was implanted as a biomaterial scaffold during perineal herniorrhaphy. Both dogs had developed severe muscle weakness, unilaterally herniated rectal protrusions, and heart problems with potential anesthetic risks. Areas affected by the perineal hernia (PH) located between the internal obturator and external anal sphincter muscles were reconstructed with naïve canine SIS sheets. In 12 months, post-operative complications such as wound infections, sciatic paralysis, rectal prolapse, or recurrence of the hernia were not observed. Symptoms of defecatory tenesmus also improved. Neither case showed any signs of rejection or specific immune responses as determined by complete and differential cell counts. Our findings demonstrate that canine SIS can be used as a biomaterial scaffold for PH repair in dogs.

Preliminary study for a newly designed silicone stent and delivery system for canine obstructive tracheal disease.

The goal of this study was to prove the possibility of using silicone stents broadly used for human medicine in canine obstructive tracheal disease. A silicone stent anatomically designed for canine trachea was tested on 5 beagle dogs for 8 weeks. The stent was carefully inserted using a newly developed delivery device under fluoroscopic guidance. There were no technical difficulties in placing the stent during the procedure. Previously reported complications of airway stenting such as stent migration or granulation tissue formation did not occur in any of the cases. In addition, removal of the stent was as simple as inserting it, and complications were absent. The stent introduced in this study could possibly be applied to various canine obstructive tracheal diseases.