Fx Group Research Articles

Fucoxanthin Enhances the Antifibrotic Potential of Placenta-derived Mesenchymal Stem Cells in a CCl4-induced Mouse Model of Liver.

The effectiveness of fucoxanthin (Fx) in liver diseases has been reported due to its anti-inflammatory and antifibrotic effects. Mesenchymal stem cells (MSCs)-based therapy has also been proposed as a promising strategy for liver fibrosis treatment. Recent studies have shown that the co-administration of MSCs and drugs demonstrates a pronounced effect on liver fibrosis. This study aimed to determine the therapeutic potential of placenta-derived MSCs (PD-MSCs) in combination with Fx to treat liver fibrosis and evaluate their impact on the main links of liver fibrosis pathogenesis. After PD-MSCs isolation and identification, outbred ICR/CD1 mice were divided into five groups: Control group, CCl4 group (CCl4), Fx group (CCl4+Fx), PD-MSCs group (CCl4+MSCs) and cotreatment group (CCl4+MSCs+Fx). Biochemical histopathological investigations were performed. Semiquantitative analysis of the alpha-smooth muscle actin (α-SMA+), matrix metalloproteinases (MMP-9+, MMP-13+), tissue inhibitor of matrix metalloproteinases-1 (TIMP-1+) areas, and the number of positive cells in them were studied by immunohistochemical staining. Transforming growth factor-beta (TGF-β), hepatic growth factor (HGF), procollagen-1 (COL1α1) in liver homogenate and proinflammatory cytokines in blood serum were determined using an enzyme immunoassay. Compared to the single treatment with PD-MSCs or Fx, their combined administration significantly reduced liver enzyme activity, the severity of liver fibrosis, the proinflammatory cytokine levels, TGF-β level, α-SMA+, TIMP-1+ areas and the number of positive cells in them, and increased HGF level, MMP-13+, and MMP-9+ areas. Fx enhanced the therapeutic potential of PD-MSCs in CCl4-induced liver fibrosis, but more investigations are necessary to understand the mutual impact of PD-MSCs and Fx.

Initial Findings Concerning the Latest Self-expandable Evolut FX Valve: A Report Using OCEAN-TAVI Registry Data

Data concerning the clinical effect of the latest-generation self-expandable transcatheter heart valve (Evolut FX) remain limited. We aimed to assess the in-hospital outcomes of 3 bioprosthetic valves (Evolut EPO, PRO+, and FX). We analyzed data from a Japanese multicenter registry involving 634 consecutive patients who underwent transcatheter aortic valve replacement with Evolut FX up until October 2023. Patients who underwent transcatheter aortic valve replacement with Evolut EPO between 2018 and 2020 (n = 1,128), and those with Evolut EPO+ between 2020 and 2023 (n = 1,696) served as the control groups. The exclusion criteria comprised patients on dialysis with a history of infective endocarditis or with insufficient data. Unmatched comparisons among the 3 valves were conducted, followed by a propensity score-matched comparison between Evolut EPO+ and FX. In the unmatched cohort, among the Evolut EPO, PRO+, and FX groups, all vascular complications (7.8% vs 5.2% vs 4.5%, respectively, p <0.01) and new pacemaker implantation rates (11.2% vs 6.1% vs 7.7%, respectively, p <0.01) differed significantly. In the propensity score-matched analysis, the rate of all bleeding events was significantly higher in the Evolut EPO+ group (11.0%) than in the FX group (7.0%) (p = 0.02), whereas all vascular complications (4.6% vs 4.6%, respectively, p = 1.00) and new pacemaker implantation (5.9% vs 7.6%, respectively, p = 0.28) rates were comparable. The incidence of stroke in the FX group was approximately half that of the EP+ group (3.7% vs 1.9%, p = 0.095), without statistical significance. In conclusion, compared with the Evolut EPO+, Evolut FX was associated with a lower incidence of in-hospital bleeding complications and may reduce the incidence of in-hospital stroke.

Evaluation of Radiation Therapy Treatment Plans in a Randomized Phase 2 Trial Comparing 2 Schedules of Twice-Daily Thoracic Radiation Therapy in Limited Stage Small Cell Lung Cancer

PurposeThere is limited clinical data for recommendations on how to deliver thoracic radiotherapy (TRT) concurrently with chemotherapy in limited stage (LS) small-cell lung cancer (SCLC). We reviewed radiotherapy treatment plans in a randomized phase II trial comparing high-dose with standard-dose twice-daily TRT to assess treatment planning techniques, dose-volume data for target volumes and organs at risk (OARs), evaluate compliance with the protocol, associations with radiation-induced toxicity and whether an imbalance in treatment planning parameters might be a reason for the large survival benefit of the higher dose (median overall survival 43.6 vs. 22.6 months). Methods and Materials170 patients were to receive four courses of platinum/etoposide and randomized to receive twice-daily TRT of 60 Gy/40 fractions (fx) or 45 Gy/30 fx. TRT treatment plans for those who received one or more fx of TRT (n=166) were analyzed. ResultsThe most common treatment planning technique was 3DCRT (67%). The 75th percentile of the reported dose-volume parameters for the OARs were within the protocol-recommended limits for both groups. Mean doses to the esophagus of 25.5 Gy (IQR: 20.2-31.3) [60 Gy/40 fx] and 24.3 Gy (IQR: 20.3-27.5) [45 Gy/30 fx] were associated with 21% and 18% ≥ grade 3 acute esophagitis, respectively. In the 60 Gy/40 fx group, a mean dose to the lungs of 16.5 Gy (IQR: 15.8-16.9), V20Gy of 29.5% (IQR: 28.8-30.4), and V5Gy of 65.6% (IQR: 61.5-68.7) led to ≥ grade 3 pneumonitis in 4% of the patients. There was no ≥ grade 3 pneumonitis in the 45 Gy group. Treatment planning techniques, the percentage change in volumes between original and re-delineated OARs, PTV volumes, relative doses, and laterality were well balanced between the randomly assigned groups. ConclusionConsidering that the incidences of severe radiation-induced toxicities were within the range of other recent trials, the reported doses to the OARs appear to be safe. Treatment planning parameters were well balanced between the randomly assigned groups, supporting that the survival benefit of the twice-daily 60 Gy/ 40 fx TRT schedule was due to the higher dose.

Prospective Randomized Phase 2 Trial of Hypofractionated Stereotactic Radiation Therapy of 25 Gy in 5 Fractions Compared With 35 Gy in 5 Fractions in the Reirradiation of Recurrent Glioblastoma

The aim of this work was to investigate whether reirradiation of recurrent glioblastoma with hypofractionated stereotactic radiation therapy (HSRT) consisting of 35 Gy in 5 fractions (35 Gy/5 fx) compared with 25 Gy in 5 fractions (25 Gy/5 fx) improves outcomes while maintaining acceptable toxicity. We conducted a prospective randomized phase 2 trial involving patients with recurrent glioblastoma (per the 2007 and 2016 World Health Organization classification). A minimum interval from first radiation therapy of 5 months and gross tumor volume of 150 cc were required. Patients were randomized 1:1 to receive HSRT alone in 25 Gy/5 fx or 35 Gy/5 fx. The primary endpoint was progression-free survival (PFS). We used a randomized phase 2 screening design with a 2-sided α of 0.15 for the primary endpoint. From 2011 to 2019, 40 patients were randomized and received HSRT, with 20 patients in each group. The median age was 50 years (range, 27-71); a new resection before HSRT was performed in 75% of patients. The median PFS was 4.9 months in the 25 Gy/5 fx group and 5.2 months in the 35 Gy/5 fx group (P = .23). Six-month PFS was similar at 40% (85% CI, 24%-55%) for both groups. The median overall survival (OS) was 9.2 months in the 25 Gy/5 fx group and 10 months in the 35 Gy/5 fx group (P = .201). Grade ≥3 necrosis was numerically higher in the 35 Gy/5 fx group (3 [16%] vs 1 [5%]), but the difference was not statistically significant (P = .267). In an exploratory analysis, median OS of patients who developed treatment-related necrosis was 14.1 months, and that of patients who did not was 8.7 months (P = .003). HSRT alone with 35 Gy/5 fx was not superior to 25 Gy/5 fx in terms of PFS or OS. Due to a potential increase in the rate of clinically meaningful treatment-related necrosis, we suggest 25 Gy/5 fx as the standard dose in HSRT alone. During follow-up, attention should be given to differentiating tumor progression from potentially manageable complications.

Digital wrist tomosynthesis (DWT)-based finite element analysis of ultra-distal radius differentiates patients with and without a history of osteoporotic fracture.

Despite effective therapies for those at risk of osteoporotic fracture, low adherence to screening guidelines and limited accuracy of bone mineral density (BMD) in predicting fracture risk preclude identification of those at risk. Because of high adherence to routine mammography, bone health screening at the time of mammography using a digital breast tomosynthesis (DBT) scanner has been suggested as a potential solution. BMD and bone microstructure can be measured from the wrist using a DBT scanner. However, the extent to which biomechanical variables can be derived from digital wrist tomosynthesis (DWT) has not been explored. Accordingly, we measured stiffness from a DWT based finite element (DWT-FE) model of the ultra-distal (UD) radius and ulna, and correlate these to reference microcomputed tomography image based FE (μCT-FE) from five cadaveric forearms. Further, this method is implemented to determine in vivo reproducibility of FE derived stiffness of UD radius and demonstrate the in vivo utility of DWT-FE in bone quality assessment by comparing two groups of postmenopausal women with and without a history of an osteoporotic fracture (Fx; n=15, NFx; n=51). Stiffness obtained from DWT and μCT had a strong correlation (R2=0.87, p<0.001). In vivo repeatability error was <5%. The NFx and Fx groups were not significantly different in DXA derived minimum T-scores (p>0.3), but stiffness of the UD radius was lower for the Fx group (p<0.007). Logistic regression models of fracture status with stiffness of the nondominant arm as the predictor were significant (p<0.01). In conclusion this study demonstrates the feasibility of fracture risk assessment in mammography settings using DWT imaging and FE modeling in vivo. Using this approach, bone and breast screening can be performed in a single visit, with the potential to improve both the prevalence of bone health screening and the accuracy of fracture risk assessment.

Simultaneous Arthroscopic Rotator Cuff Repair and Glenoid Microfracture in Active-Duty Military Patients Younger Than 50 Years: Outcomes at Midterm Follow-up.

While concomitant full-thickness rotator cuff tears and glenoid osteochondral defects are relatively uncommon in younger patients, military patients represent a unique opportunity to study this challenging injury pattern. To compare the outcomes of young, active-duty military patients who underwent isolated arthroscopic rotator cuff repair (ARCR) with those who underwent ARCR plus concurrent glenoid microfracture (ARCR+Mfx). It was hypothesized that ARCR+Mfx would produce significant improvements in patient-reported outcome measures. Cohort study; Level of evidence, 3. This was a retrospective analysis of consecutive active-duty military patients from a single base who underwent ARCR for full-thickness rotator cuff tears between January 2012 and December 2020. All patients were <50 years and had minimum 2-year follow-up data. Patients who underwent ARCR+Mfx were compared with those who underwent isolated ARCR based on the visual analog scale (VAS) for pain, Single Assessment Numeric Evaluation (SANE), American Shoulder and Elbow Surgeons (ASES) shoulder score, and range of motion. A total of 88 patients met the inclusion criteria for this study: 28 underwent ARCR+Mfx and 60 underwent isolated ARCR. The mean final follow-up was 74.11 ± 33.57 months for the ARCR+Mfx group and 72.87 ± 11.46 months for the ARCR group (P = .80). There were no differences in baseline patient characteristics or preoperative outcome scores between groups. Postoperatively, both groups experienced statistically significant improvements in all outcome scores (P < .0001 for all). However, the ARCR+Mfx group had significantly worse VAS pain (1.89 ± 2.22 vs 1.03 ± 1.70; P = .05), SANE (85.46 ± 12.99 vs 91.93 ± 12.26; P = .03), and ASES (86.25 ± 14.14 vs 92.85 ± 12.57; P = .03) scores. At the final follow-up, 20 (71.43%) patients in the ARCR+Mfx group and 53 (88.33%) patients in the ARCR group were able to remain on unrestricted active-duty military service (P = .05). Concomitant ARCR+Mfx led to statistically and clinically significant improvements in patient-reported outcome measures at the midterm follow-up. However, patients who underwent ARCR+Mfx had significantly worse outcomes and were less likely to return to active-duty military service than those who underwent isolated ARCR. The study findings suggest that ARCR+Mfx may be a reasonable option for young, active patients who are not candidates for arthroplasty.

The Effect of Stereotactic Body Radiotherapy (SBRT) Dose-Fraction (fx) Schema on Non-Small Cell Lung Cancer (NSCLC)

Stereotactic body radiotherapy (SBRT) dose-fraction (fx) schema for non-small cell lung cancer (NSCLC) varies at different centers and commonly involves 3 to 5 fx. Additionally, the frequency of treatment per week, or treatment schedules (TS), can also differ. We sought to evaluate and compare the effect of different dose-fx schemas on overall survival (OS). We retrieved data from the National Cancer Database. Patient eligibility included early-stage NSCLC with cT1-2 N0M0 disease treated with SBRT using 3-5f x regimens. Demographics and clinical characteristics were identified. Biologically effective dose (BED) and total dose (TD) were calculated. TD included following: 45-60 Gy for 3 fx, 48-60 Gy for 4 fx, and 50-60 Gy for 5 fx. TS was classified as one of the following: daily, every other day, twice per week, or prolonged (less frequently than twice weekly). Non-prolonged TS was defined as daily, every other day, and twice per week. OS was calculated from the date of end of RT to the date of death and censored at the date of last contact. Kaplan Meier method was used to estimate OS and log-rank tests were used to compare the difference between groups. TS was compared pairwise within each individual fx-group. Univariable Cox proportional models with robust standard errors to account for within institution correlations were used to investigate the association between BED, TD, TS, fx-group and OS. Within each fx-group, BED was also assessed and compared. A total of 3244 patients were identified, with median age 73. 48% were males and 52% females. 601 (19%) patients received 3 fx, 884 (27%) received 4 fx, and 1759 (54%) received 5 fx treatments. For the overall cohort, median and mean BEDs were 112 and 119, respectively. TS did not show a difference in OS among each individual fx group. Overall, prolonged vs non-prolonged schedules also did not show a difference in OS (p = 0.64). OS was superior in the 3 fx group compared to 4 and 5 fx groups, with median survival times of 61.5 vs 53.7 vs 52.6 months, respectively (p = 0.046). Overall, an increase in BED reduced risk of death (HR = 0.97 per 10-units, CI: 0.94-0.99, p = 0.04). When stratified by fx, each 10 unit rise in BED for those treated with 5 fx reduced the risk of death by 8% (HR = 0.92, CI: 0.87-0.97, p<0.01). However, increasing BED was not associated with change in OS for 3 fx (HR = 1.00, CI: 0.93-1.08, p = 0.93) and 4 fx (HR = 1.08, p = 0.08) regimens. Patients who received BED greater than the median (BED>112) had improved OS compared to those receiving BED£112 (HR = 0.86, p = 0.047). When evaluating the 5 fx-group individually, BED >100 (median of 5fx group) had superior OS compared to £100 (HR = 0.80, p = 0.02). Three-fraction regimens have superior OS compared to 4 and 5 fx regimens. Higher BED improves OS in 5 fx regimens. Treatment schedule variations among individual fx-groups does not impact OS.

Bee Pollen Stimulated BMP2 and RANK Signaling Pathway in Osteoprogenitors and Improved Bone Mineralization in Rat Model of Femur Fracture

Objectives Bee pollen (BP) contains isoflavonoids and minerals that can be effective in bone repair, stimulation of osteoprogenitors, differentiation of osteoblasts, and inhibition of osteoclasts. For this purpose, in the present study, BP was used to stimulate osteogenesis in an animal model of a femur fracture. Materials and Methods After induction of the femur fracture model, 80 Wistar rats in eight groups ( n = 10) were studied as follows. Normal control group (0.5 cc of distilled water, DW/gavage/90 days), BP group (200 mg/kg BP/daily/gavage/90 days), fracture (FX-0.5 cc of distilled water/gavage/90 days), FX group treated with 100 and 200 mg/kg BP (100 and 200 mg/kg BP/daily/gavage/90 days), FX group treated with osteocare (OC) syrup (1 mL/day/gavage/90 days) and combinatorial FX groups treated with BP and OC syrup (100 and 200 mg/kg BP plus 1 mL OC/daily/gavage/90 days). On the 30th, 60th, and 90th days, radiography of the lesion was done. Bone mineral density (BMD) was measured by dual-energy X-ray absorptiometry during the mentioned days. At the end of the study, blood calcium (Ca), phosphorus (P), and alkaline phosphatase (ALP), along with the activity of glutathione peroxidase (GPx), superoxide dismutase (SOD), and catalase (CAT) enzymes, and nitric oxide levels, were measured. Calcitonin and parathyroid hormone levels were measured with enzyme-linked immunosorbent assay (ELISA) kits. In order to evaluate the stimulation of osteoprogenitors, the expression of osteoprotegerin (OPG), receptor activator of nuclear factor kappa-B (RANK), receptor activator of nuclear factor kappa-B ligand (RANKL), and bone morphogenetic protein-2 (BMP-2) genes and proteins in bone tissue was measured. Results The evaluations of this study showed that BP could improve BMD parameters through stimulation of the OPG/RANK/BMP-2 pathway. BP also improved serum levels of biochemical factors (Ca, P, and ALP) and hormones related to osteogenesis. Conclusion BP can be used for bone fractures and disorders related to osteoporosis.

Hip structure analysis and femoral osteodensitometry in aged postmenopausal women with hip osteoarthritis and femoral neck fracture.

Osteoarthritis (OA), osteoporosis, and bone fractures are frequent aging-related conditions. Regardless of the growing research interest in the effects of hip OA on femoral fracture risk, data about the region specificity of osteodensitometric and hip structure analysis (HSA) parameters of the proximal femora are lacking in aged postmenopausal women with hip OA compared to individuals with femoral neck fragility fracture. This study included 76 postmenopausal women admitted for total hip arthroplasty due to non-traumatic femoral neck fracture (FN_Fx group, n = 39) and hip osteoarthritis (OA group, n = 37). Osteodensitometric parameters differed significantly between the OA and FN_Fx groups, depicting lower bone mineral density in the FN_Fx group (p < 0.05). The most significant increase in these parameters was registered in the intertrochanteric region of the OA group. Moreover, the OA-induced changes in HSA-derived parameters displayed significant regional heterogeneity, with the intertrochanteric region showing the most notable difference between OA and FN_Fx group. Our data may indicate that OA displayed the most prominent positive effect on the intertrochanteric femoral region, revealing the regional heterogeneity in structural geometry and biomechanical indices of proximal femora in OA individuals. Since we did not observe significant differences in the femoral neck region, we may speculate that OA does not have a substantial protective effect on the femoral neck fracture risk in aged postmenopausal women.

Appropriateness of Replacing Fluoroscopic Guidance With ECG-Electromagnetic Guidance for PICC Insertion: A Randomized Controlled Trial.

OBJECTIVE. Coupled ECG-electromagnetic (EM) guidance shows promise for use in placement of peripherally inserted central catheters (PICCs) when compared with the classic blind technique. However, ECG-EM guidance has not been appropriately compared with the reference standard of fluoroscopy (FX) guidance. Here, we aimed to compare ECG-EM guidance with FX guidance with regard to the final tip position of PICCs. SUBJECTS AND METHODS. A total of 120 patients (age range, 19-94 years) referred for PICC placement were randomized to the ECG-EM or FX group. All interventions were performed by PICC team members who had the same standardized training and experience. Final tip position was assessed using chest radiography and was classified as optimal, suboptimal, or inadequate requiring repositioning on the basis of the distance from the PICC tip to the cavoatrial junction (CAJ). Statistical analyses were performed using the Mann-Whitney U test for final catheter tip position (mean distance from CAJ) and Fisher and chi-square tests for proportions. RESULTS. PICCs were successfully inserted in 118 patients (53 men and 65 women). Catheter tip positions were optimal or suboptimal in 100% of the FX group and 77.2% of the ECG-EM group. Furthermore, precision of placement was significantly better (p = .004) in the FX group (mean distance from the PICC tip to the CAJ = 0.83 cm) than in the ECGEM group (mean distance from the PICC tip to the CAJ = 1.37 cm). Thirteen (22.8%) of the PICCs placed using ECG-EM guidance, all of which were inserted from the left side, were qualified as inadequate requiring repositioning and required another intervention. CONCLUSION. Our results revealed significant differences in final tip position between the ECG-EM and FX guidance techniques and indicate that ECG-EM guidance cannot appropriately replace FX guidance among unselected patients. However, ECGEM guidance could be considered as an acceptable technique for patients in whom the PICC could be inserted from the right side. TRIAL REGISTRATION. ClinicalTrials.gov NCT03652727.

Preventive effect of fucoxanthin administration on intra-abdominal adhesion: An experimental animal study.

The most common cause of intra-abdominal adhesion (IAA) is previous abdominal surgery and mortality. IAA can cause serious complications such as chronic abdominal pain, ileus, and infertility. Approximately 3% of all laparotomies are related to adhesions. IAA reduces the quality of life of the patient, causes morbidity, and increases health expenditures. In this study, we aimed to investigate the preventive effect of fucoxanthin (Fx) on IAA in the intra-abdominal surgical adhesion model that experimentally created in rats. This study used 21 Sprague-Dawley rats divided into three groups. After anesthesia, the abdomen was opened, the cecum and right abdominal wall were damaged with a sterile toothbrush until petechiae bleeding was seen. No additional action was taken to the control group. In the sham group, 5 cc saline solution was released into the peritoneum before the abdomen was closed. In the Fx group, 35 mg/kg Fx was instilled intraperitoneally and the abdomen was closed. On the 21st post-operative day, all subjects were anesthetized with standard anesthesia. Macroscopic adhesions were quantitatively evaluated according to the Mazuji classifica-tion. The cecum anterior wall and parietal peritoneum were excised for pathological sampling. A pathologist, unaware of the groups, evaluated inflammation, fibroblastic activity, and vascular proliferation. In addition, serum tumor necrosis factor-alpha (TNF-α) and interleukin-10 levels were measured. No rat was lost during the study period. Congenital adhesion was not observed in any of the subjects at the first laparo-tomy. Adhesion was significantly less macroscopically in the Fx group compared to the control and sham group (p<0.001 and p<0.001). Fibroblastic activity was found to be significantly less in the Fx group compared to the sham and control groups (p<0.001 and p<0.001). Vascular proliferation was found to be significantly less in the Fx group than in the sham and control groups (p<0.001 and p<0.001). The inflammation score was significantly lower in the Fx group compared to the other two groups (p<0.001 and p<0.001). The inflam-mation score in the sham group was lower than the control group and was statistically significant (p<0.001). TNF-α level was found to be statistically significantly lower in the Fx group compared to the sham and control groups (p<0.001 and p<0.001). As a result of experimental study, we can say that Fx is effective in preventing IAAs and decreases the level of TNF-α, a pro-inflammatory cytokine.

Magnitude, Specificity, and Avidity of Sporozoite-Specific Antibodies Associate With Protection Status and Distinguish Among RTS,S/AS01 Dose Regimens

Abstract Background The malaria vaccine, RTS,S/AS01, demonstrated an enhanced efficacy (86.7%) in a delayed third fractional dose (0.1.7Fx) regimen in controlled human malaria infection trials compared with a standard full-dose (0.1.2) regimen (62.5%). To understand the humoral component of the RTS,S/AS01 vaccine-induced protection against sporozoite infection in these 2 regimens, we investigated the serum antibody dynamics of 0.1.2 and 0.1.7Fx groups vaccinees. Methods The specific binding responses (magnitude) and dissociation rates (avidity) of serum antibodies interaction with a recombinant Plasmodium falciparum circumsporozoite protein (CSP) and peptides corresponding to the central repeat region (NANP6), the C-terminal region (PF16), and the N-terminal junction (N-interface) of CSP, respectively, were measured using a Biolayer Interferometry assay. Results On the day of challenge, higher NANP6-specific antibody responses were associated with protection in the 0.1.2 group. In contrast, slower antibody dissociation rates for CSP and PF16 binding were observed in the protected 0.1.7Fx group. Protected vaccinees of both groups exhibited 2- to 3-fold higher N-interface peptide binding antibody responses. Conclusions Unlike the standard dose, the delayed-fractional third dose of RTS,S/AS01 induced higher avidity CSP and PF16 binding antibodies that were associated with protection against sporozoite infection.

Noncultured Minimally Processed Adipose-Derived Stem Cells Improve Radiated Fracture Healing.

Adipose-derived stem cells mitigate deleterious effects of radiation on bone and enhance radiated fracture healing by replacing damaged cells and stimulating angiogenesis. However, adipose-derived stem cell harvest and delivery techniques must be refined to comply with the US Food and Drug Administration restrictions on implantation of cultured cells into human subjects prior to clinical translation. The purpose of this study is to demonstrate the preservation of efficacy of adipose-derived stem cells to remediate the injurious effects of radiation on fracture healing utilizing a novel harvest and delivery technique that avoids the need for cell culture. Forty-four Lewis rats were divided into 4 groups: fracture control (Fx), radiated fracture control (XFx), radiated fracture treated with cultured adipose-derived stem cells (ASC), and radiated fracture treated with noncultured minimally processed adipose-derived stem cells (MP-ASC). Excluding the Fx group, all rats received a fractionated human-equivalent dose of radiation. All groups underwent mandibular osteotomy with external fixation. Following sacrifice on postoperative day 40, union rate, mineralization, and biomechanical strength were compared between groups at P < 0.05 significance. Compared with Fx controls, the XFx group demonstrated decreased union rate (100% vs 20%), bone volume fraction (P = 0.003), and ultimate load (P < 0.001). Compared with XFx controls, the MP-ASC group tripled the union rate (20% vs 60%) and demonstrated statistically significant increases in both bone volume fraction (P = 0.005) and ultimate load (P = 0.025). Compared with the MP-ASC group, the ASC group showed increased union rate (60% vs 100%) and no significant difference in bone volume fraction (P = 0.936) and ultimate load (P = 0.202). Noncultured minimally processed adipose-derived stem cells demonstrate the capacity to improve irradiated fracture healing without the need for cell proliferation in culture. Further refinement of the cell harvest and delivery techniques demonstrated in this report will enhance the ability of noncultured minimally processed adipose-derived stem cells to improve union rate and bone quality, thereby optimizing clinical translation.

Dietary Fucoxanthin Induces Anoikis in Colorectal Adenocarcinoma by Suppressing Integrin Signaling in a Murine Colorectal Cancer Model.

Fucoxanthin (Fx), abundantly contained in edible brown algae, is a carotenoid with strong anti-cancer potential. Anoikis is an anchor-dependent apoptosis particularly related to integrin signaling, and a target for cancer preventive strategies. We recently demonstrated that Fx prevented colon cancer in azoxymethane-dextrane sodium sulfate (AOM/DSS) carcinogenic model mice, and that it increased anoikis-like integrin β1low/-/cleaved caspase-3high cells in colonic mucosal crypts. However, an induction mechanism of anoikis by Fx in adenocarcinoma tissue remains unresolved. Thus, we investigated anoikis in colonic adenocarcinoma in AOM/DSS mice. Fx administration (30 mg/kg body weight) significantly suppressed the incidence and multiplicity of colonic adenocarcinoma in AOM/DSS mice. A number of anoikis-like integrin β1low/-/cleaved caspase-3high cells in colonic adenocarcinoma and mucosal crypts were significantly increased, 8.3- and 3.5-fold in the Fx group compared with those of the control group, respectively. The results indicated the increase of anoikis-like cells occurred more strongly in colonic adenocarcinoma than in colonic mucosal crypts. In addition, integrin β1 expression, and pFAK (Tyr397) and pPaxillin (Tyr31) activation in mucosal tissue decreased 0.7-, 0.5- and 0.6-fold by Fx administration, respectively. The results suggest that Fx induces anoikis in colonic adenocarcinoma developed by AOM/DSS treatment through attenuation of integrin signaling.

Preventive Effects of Fucoidan and Fucoxanthin on Hyperuricemic Rats Induced by Potassium Oxonate.

The purpose of this study was to investigate the preventive effects of fucoidan (Fc) and fucoxanthin (Fx) on hyperuricemic rats. Sprague Dawley (SD) rats were randomly assigned to seven groups: a control group, a hyperuricemia (HUA) group, low- and high-dose Fx groups, a Fc group, a combination Fc and Fx group, and a positive control group. Three weeks after the interventions, each group was given potassium oxonate (PO) and hypoxanthine (HX) to induce HUA in all groups except for the control group, and the rats were then sacrificed. Blood and urine were analyzed for biochemical properties, and differences in urine volume were determined. Livers and kidneys were collected to analyze xanthine oxidase (XO) activity and the expression of uric acid (UA) transporter-related proteins (GLUT9, ABCG2, OAT1, URAT1). The results show that HUA was successfully induced by PO/HX after 4 h of administration. The activity of XO was significantly reduced by a combination of Fc and Fx. In the combination group, both ABCG2 and OAT1 increased significantly, whereas GLUT9 and URAT1 decreased significantly. In summary, the combination of Fc and Fx can inhibit the activity of XO in the liver and regulate the expression of proteins related to UA transporter in the kidney to reduce the UA level in serum.

Comparison and Clinical Evaluation of Two Pit and Fissure Sealants on Permanent Mandibular First Molars: An In Vivo Study

The aim of the study was to compare and evaluate the clinical efficacy of a microfilled pit and fissure sealant and a nanofilled pit and fissure sealant at 3, 6, and 12 months of interval. Samples consisting of 55 healthy 8- to 12-year-old children with deep pits and fissures in mandibular first permanent molars were selected for the study. It was a split mouth design and randomized clinical trial. A total of 110 mandibular first molars were divided into two groups of 55 each: group I Fissurit FX sealant and group II Grandioseal nanofilled fissure sealant. The sealed teeth were clinically evaluated at 3, 6, and 12 months of interval to assess marginal adaptation, sealant retention, fissure caries development, roughness of sealant surface, and change of color around the sealant. The results showed that both Fissurit FX and Grandioseal pit and fissure sealants were effective in preventing dental caries. Marginal adaptation was significantly better with Fissurit FX when compared to Grandioseal pit and fissure sealant. There was no difference in sealant retention between the two groups. The surface roughness of Fissurit FX was high when compared to that of Grandioseal. Statistical analysis was done using the Chi-squared test for intra-group comparison and Fisher's exact test for inter-group comparison. Results were considered statistically significant if p ≤ 0.05. Fissurit FX and Grandioseal pit and fissure sealants provided similar caries preventive effects and there was no difference in retention of sealants over a period of 1 year. However, surface roughness was better with Grandioseal fissure sealants. This study is significant because there is limited evidence about the efficacy of nanofilled pit and fissure sealants in vivo. It will also provide dental practitioners an insight into the clinical efficacy of nanofilled pits and fissure sealant when compared to micro-filled sealant enabling them to make the right choice for the betterment of their dental practice. How to cite this article: Smitha M, Paul ST, Nagaraj T, et al. Comparison and Clinical Evaluation of Two Pit and Fissure Sealants on Permanent Mandibular First Molars: An In Vivo Study. J Contemp Dent Pract 2019;20(10):1151-1158.

Anti-Oxidative and Neuroprotective Effects of Supplementary Flaxseed on Oxidative Damage in the Hippocampus Area of a Rat Model of Hypoxia

Background: During hypoxia, the increased production of reactive oxygen species occurs during the re-oxygenation phase of periodic continuous hypobaric hypoxia. Objectives: In this study, we surveyed the effect of supplementary flaxseed (Fx) on oxidative damage to the hippocampus of the hypoxic rat model. Methods: In this study, 24 adult Wistar rats were randomly divided and studied in four groups: (1) The control group with normal oxygen and food (Co.), (2) The sham group placed in a hypoxia chamber with normal oxygen and food (Sh.), (3) Hypoxia induction group with normal food (Hx), and (4) Hypoxia induction group with 10% Fx food (Hx + Fx). Both the Hx and Hx + Fx groups were kept in a hypoxic chamber for 30 days while the atmospheric pressure was reduced (oxygen 8%, nitrogen 92%) for four hours daily. Malondialdehyde (MDA) and total antioxidant capacity (TAC) levels were evaluated in the hippocampus region of the brain tissue. Neuronal damage was examined using histological studies. Blood samples were collected to measure interleukin-18 (IL-18). Results: A significant increase was recorded in the IL-18 level and hippocampal dark neurons of the CA1, CA2, CA3, and dentate gyrus (DG) areas in the Hx group as compared to Co. and Sh. groups (P < 0.05). Moreover, a significant decrease was noted in the dark neurons in the Hx + Fx group as compared to the Hx group (P < 0.05). A significant increase was observed in the TAC concentration in the Hx + Fx group in comparison with the Co., Sh., and Hx groups (P < 0.05), while a significant increase was observed in the MDA concentration in the Hx group as compared to the Co. and Sh. groups and a significant decrease in the Hx + Fx group as compared to the Hx group (P < 0.05). Conclusions: This study suggested that the consumption of flaxseed could be a useful strategy for preventing the harmful effect of hypoxia on the hippocampus of the rat brain.

Flaxseed Can Reduce Hypoxia-Induced Damages in Rat Testes.

BackgroundHypoxia causes detrimental effects on the structure and function of tissues through increased production of reactive oxygen species that are generated during the re-oxygenation phase of intermittent and continuous hypobaric hypoxia. This study was carried out to evaluate the effects of flaxseed (Fx) in reducing the incidence of hypoxia in rat testes.Materials and MethodsIn this experimental study, 24 adult Wistar rats were randomly divided into four groups: i. Control group (Co) that received normal levels of oxygen and food, ii. Sham group (Sh) that were placed in hypoxia chamber but received normal oxygen and food, iii. Hypoxia induction group (Hx) that were placed in hypoxia chamber and treated with normal food, iv. Hypoxia induction group (Hx+Fx) that were placed in hypoxia chamber and treated with 10% flaxseed food. Both the Hx and Hx+Fx groups were kept in a hypoxic chamber for 30 days; during this period rats were exposed to reduced pressure (oxygen 8% and nitrogen 92%) for 4 hours/day. Then, all animal were sacrificed and their testes were removed. Malondialdehyde (MDA) and total antioxidant capacity (TAC) levels were evaluated in the testis tissue. Tubular damages were examined using histological studies. Blood samples and sperm were collected to assess IL-18 level and measure sperms parameters, respectively. All data were analyzed using SPPSS-22 software. One way-ANOVA or Kruskal-Wallis tests were performed for statistical analysis.ResultsA significant difference was recorded in the testicular mass/body weight ratio in Hx and Hx+Fx groups in comparison to the control (P=0.003 and 0.027, respectively) and Sh (P=0.001 and 0.009, respectively) groups. The sperm count and motility in Hx+Fx group were significantly different from those of the Hx group (P=0.0001 and 0.028, respectively) .Also sperm viability (P=0.0001) and abnormality (P=0.0001) in Hx+Fx group were significantly different from Hx group.ConclusionThis study therefore suggests that the oral administration of flaxseed can be useful for prevention from the detrimental effects of hypoxia on rat testes structure and sperm parameters.

Severe Hemorrhagic Shock Leads to a Delayed Fracture Healing and Decreased Bone Callus Strength in a Mouse Model.

Multiple trauma is frequently associated with hemorrhagic shock and fractures of the extremities. Clinically, the rate of impaired fracture healing (delayed healing and nonunion) seems to be increased in patients with multiple injuries compared with patients with isolated fractures. As the underlying pathogenesis remains poorly understood, we aimed to analyze the biomechanical properties during fracture healing in a murine model. The aim of this study was to determine whether fracture healing after severe hemorrhagic shock results in (1) delayed bridging as determined by macroscopic and radiographic assessment, (2) altered conditions of callus components as determined by µCT, and (3) decreased maximum bending moment measured by a three-point-bending test compared with ordinary fracture healing. Male C57BL/6NCrl mice were randomly assigned to five groups and four different times (five to 10 mice per group and time). Only the right femur from each mouse was used for analysis: the trauma hemorrhage (TH) group received a pressure-controlled hemorrhagic shock via catheter; the osteotomy (Fx) group underwent osteotomy and implantation of an external fixator on the right femur; the combined trauma (THFx) group received hemorrhagic shock and an external fixator with osteotomy; the sham group underwent implantation of a catheter and external fixator but had no blood loss or osteotomy, and the control group underwent no interventions. After 2, 3, 4, or 6 weeks, five to 10 animals of each group were sacrificed. Bones were analyzed macroscopically and via radiographs, µCT, and three-point-bending test. Statistical significance was set at a probability less than 0.05. Comparisons were performed using the Mann-Whitney U or the Kruskal-Wallis test. In the Fx group, the osteotomy gap was stable and bridged after 2 weeks in contrast to some bones in the THFx group where stable bridging did not occur. No difference was observed between the groups. µCT analysis showed reduced density of bone including callus (THFx: 1.17 g/cm3; interquartile range [IQR], 0.04 g/cm3; Fx: 1.22 g/cm3; IQR, 0.04 g/cm3; p=0.002; difference of medians [DM], -0.048; 95% CI, -0.073 to -0.029) and increased share of callus per volume of bone mass (%) after 2 weeks in the THFx group compared with the Fx group (THFx: 44.16%; IQR, 8.66%; Fx: 36.73%; IQR, 4.39%; p=0.015; DM, 7.634; 95% CI, 2.018-10.577). The three-point-bending test established a decreased maximum bending moment in the THFx group compared with the Fx group 2 weeks after surgery (THFx: 7.10 Nmm; IQR, 11.25 Nmm; Fx: 11.25 Nmm; IQR, 5.70 Nmm; p=0.026; DM, -5.043; 95% CI, -10.867 to -0.74). No differences were observed between the THFx and Fx groups after more than 2 weeks. In this in vivo mouse fracture model, we conclude that hemorrhagic shock retards fracture healing during the early phase of the facture healing process. A severe hemorrhagic shock in patients could result in initial delayed fracture healing and needs special attention. We plan to conduct a prospective, observational clinical research study to analyze if delayed fracture healing occurs in patients after severe blood loss.

H-Reflex Plasticity Following Cast Immobilization Of Distal Radius Wrist Fractures

The Hoffmann (H)-reflex has been used as a recovery marker in disuse-immobilization models. The data is limited on the effects of forearm immobilization on the H-reflex, especially in clinical populations. PURPOSE: To determine H-reflex changes following a distal radius wrist fracture requiring cast immobilization. METHODS: Five fracture (FX) patients (4 W; 1 M; age: 45.2±18.9 yrs; ht: 164.1±7.0 cm; wt: 64.4±4.9 kg) and five uninjured age-matched controls (CON) (4 W; 1 M; age: 44.6±17.3 yrs; ht: 171.5±5.5 cm; wt: 68.9±8.8 kg) were enrolled. FX group was measured four times up to 12-weeks post fracture; the CON group was tracked over the same period, with measures taken at least three weeks apart. Hmax and Mmax were elicited in the flexor carpi radialis (FCR) of each arm via stimulation of the median nerve (0.5 ms pulse) under a 10% maximal voluntary contraction (MVC). A recruitment curve was built using 0.5 mA increments. Measures included wrist flexion (WF) torque (dynamometer), peak electromyography (EMG) amplitude normalized to Mmax, grip strength, range of motion (ROM; goniometry), muscle thickness (MT; ultrasound), and function via Patient-Rated Wrist Evaluation (PRWE). RESULTS: In the fractured limb, Hmax:Mmax amplitude ratio (23.0±16.1 to 23.1±12.0%) did not change over time (p > 0.05), but Hmax:Mmax stimulation ratio significantly decreased: 70.5±2.9% to 63.1±4.5% (p < 0.05). WF increased during recovery (6.4±1.2 to 8.5±2.3 Nm; p < 0.05), but normalized EMG during MVC showed a decreasing trend from 18.3±6.4 to 13.8±9.6% Mmax (p = 0.054). Time main effects were also evident for MT (2.7±0.5 to 3.2±0.5cm; p < 0.05), grip strength (6.0±6.8 to 19.6±8.5kg; p < 0.001), wrist ROM (87.9±18.7 to 119.4±20.5°; p < 0.05), and PRWE (84±24 to 28±32 score; p < 0.001), all reflecting incomplete recovery up to 12-weeks post fracture. No significant differences were shown for the uninjured arm of FX group or in any measures for CON, except WF MVC (24.7±7.2 to 22.0±6.9Nm; p < 0.05). CONCLUSION: Although peak amplitude of the H-reflex did not change during recovery, decreased intensity needed to evoke Hmax could reflect changes to the excitability of spinal circuitry after wrist fracture. These data have important therapeutic implications for understanding how the nervous system is impacted after wrist fracture and cast immobilization.