scholarly journals 168. Efficacy of the Novel gwt1 Inhibitor APX2039 in a Rabbit Model of cryptococcus Meningitis

2020 ◽  
Vol 7 (Supplement_1) ◽  
pp. S213-S213
Author(s):  
Karen J Shaw ◽  
Charles D Giamberardino ◽  
Quinlyn A Soltow ◽  
Jennifer Tenor ◽  
Dena Toffaletti ◽  
...  
Keyword(s):  
Brain Tissue ◽  
Oral Treatment ◽  
Treatment Options ◽  
Rabbit Model ◽  
Experimental Period ◽  
Control Group ◽  
Log10 Reduction ◽  
Research Support ◽  
Rapid Reduction ◽  
Geographical Regions

Abstract Background Cryptococcal meningitis (CM), caused primarily by Cryptococcus neoformans, is uniformly fatal if not treated. Treatment options are limited especially in resource-poor geographical regions, and mortality rates remain high despite current therapies. New oral treatment options are needed that demonstrate rapid reductions in CFU in CSF and brain tissue. APX2039 is a novel inhibitor of the fungal Gwt1 enzyme, which catalyzes an early step in glycosylphosphatidyl inositol (GPI) anchor biosynthesis. It is highly active against both C. neoformans and C. gattii and has previously demonstrated significant efficacy in a mouse delayed-treatment model of CM. CSF Fungal Burden in Rabbits Methods Male New Zealand White rabbits were inoculated with C. neoformans H99 (1.4 ×106 CFU) directly into the cisterna magna. Rabbits were immunosuppressed with cortisone acetate at 7.5 mg/kg (i.m.), starting on Day -1 relative to inoculation and then administered drug daily throughout the 14-day experimental period. Treatment was initiated on Day 2 postinfection and continued through Day 14 consisting of: 50 mg/kg APX2039 PO (BID), 80 mg/kg fluconazole (FLU) PO (QD), c) 1 mg/kg amphotericin B deoxycholate (AMB) IV (QD); and vehicle control. CSF was removed via an intracisternal tap on Days 2, 7, 10 and 14 post-infection and CFU/ml was assessed. Animals were sacrificed on Day 14 and CFU/g brain tissue was assessed. Results APX2039 demonstrated rapid reduction in CFU in both CSF and brain tissue. The range in CFU values in rabbit CSF is shown (Figure). Reductions in CFU were statistically different from the control group for all treatment groups. APX2039 was also different from both FLU and AMB and resulted in sterilization in CSF by Day 10. Brain harvested on Day 14 demonstrated a reduction in CFU/g tissue vs control of 1.8 log10 and 3.4 log10 for FLU and AMB, respectively, while a > 6 log10 reduction (tissue sterilization) was observed for APX2039. Conclusion APX2039 demonstrated potent efficacy in a rabbit model of CM. The more rapid clearance in CSF than either AMB or FLU, as well as > 6 log10 reduction in brain CFU highlights the unique properties of this drug, warranting further investigation of this molecule for the treatment of CM. Disclosures Karen J. Shaw, PhD, Amplyx (Consultant)Forge Therapeutics (Consultant) Charles D. Giamberardino, Jr., MR, Box (Shareholder) John R. Perfect, MD, amplyx (Grant/Research Support)astellas (Grant/Research Support)astellas (Grant/Research Support)

scholarly journals In VitroandIn VivoEvaluation of APX001A/APX001 and Other Gwt1 Inhibitors againstCryptococcus

2018 ◽  
Vol 62 (8) ◽  
Author(s):  
Karen Joy Shaw ◽  
Wiley A. Schell ◽  
Jonathan Covel ◽  
Gisele Duboc ◽  
C. Giamberardino ◽  
...  
Keyword(s):  
Brain Tissue ◽  
Lung Tissue ◽  
Fungal Infections ◽  
Treatment Options ◽  
Content Type ◽  
Fungal Burden ◽  
Geographical Regions ◽  
Current Therapies

ABSTRACTCryptococcal meningitis (CM), caused primarily byCryptococcus neoformans, is uniformly fatal if not treated. Treatment options are limited, especially in resource-poor geographical regions, and mortality rates remain high despite current therapies. Here we evaluated thein vitroandin vivoactivity of several compounds, including APX001A and its prodrug, APX001, currently in clinical development for the treatment of invasive fungal infections. These compounds target the conserved Gwt1 enzyme that is required for the localization of glycosylphosphatidylinositol (GPI)-anchored cell wall mannoproteins in fungi. The Gwt1 inhibitors had low MIC values, ranging from 0.004 μg/ml to 0.5 μg/ml, against bothC. neoformansandC. gattii. APX001A and APX2020 demonstratedin vitrosynergy with fluconazole (fractional inhibitory concentration index, 0.37 for both). In a CM model, APX001 and fluconazole each alone reduced the fungal burden in brain tissue (0.78 and 1.04 log10CFU/g, respectively), whereas the combination resulted in a reduction of 3.52 log10CFU/g brain tissue. Efficacy, as measured by a reduction in the brain and lung tissue fungal burden, was also observed for another Gwt1 inhibitor prodrug, APX2096, where dose-dependent reductions in the fungal burden ranged from 5.91 to 1.79 log10CFU/g lung tissue and from 7.00 and 0.92 log10CFU/g brain tissue, representing the nearly complete or complete sterilization of lung and brain tissue at the higher doses. These data support the further clinical evaluation of this new class of antifungal agents for the treatment of CM.

Effect of dietary probiotic, antibiotic or combination on broiler performance, cecum microbial population and ileal development

2020 ◽  
Vol 21 (3) ◽  
pp. 74-79
Author(s):  
Ahmed Elbaz ◽  
Said El-sheikh
Keyword(s):  
Control Diet ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Experimental Period ◽  
Nutrient Digestibility ◽  
Lipoprotein Cholesterol ◽  
Control Group ◽  
Gut Health ◽  
Feed Conversion ◽  
Broiler Performance

Objective: To investigate the effect of antibiotics and/or probiotics on broiler performance, some serum metabolites, cecum microflora composition, and ileum histomorphology under the Egyptian conditions. Design: Randomized controlled experimental study. Animals: Two hundred forty 1-day-old Ross (308) chicks were reared till 35 days of age. Procedures: The birds were randomly allocated into four main groups: a control diet without additives (CON); probiotic (Lactobacillus acidophilus) supplemented diet (PRO); antibiotic (Avilamycin) supplemented diet (ANT) and a mix group (AP) that received antibiotic in the diet form 1 to 4 days of age and treated during the rest of the experimental period with probiotics. Results: Chickens fed on probiotic or antibiotic diets had linear improvement in live body weight (LBW) and feed conversion ratio (FCR) compared with the control group, while the best LBW and FCR were in the AP group. An improvement in the nutrient digestibility was observed in the probiotic added groups (PRO and AP). Serum cholesterol and low-density lipoprotein cholesterol contents decreased when antimicrobial (probiotic or antibiotic) supplementations were used, while there was an increase in high-density lipoprotein cholesterol contents, serum total protein, and albumin levels. Among all groups, cecum Clostridium perfringens and Escherichia coli counts decreased; however, there was an increase in Lactobacillus count compared to the control group. In probiotic supplemented groups (PRO and AP), a significant (P<0.05) improvement in ilea architecture. Conclusion and clinical relevance: Using probiotic after initial treatment with an antibiotic in broiler diets had a positive effect on broiler growth performance, gut health (improved cecum microbial populations and ileum histomorphology), and nutrient digestibility.

Proteomic Analysis of the Vitreous Body in Proliferative and Non-Proliferative Diabetic Retinopathy

2020 ◽  
Vol 17 ◽  
Author(s):  
Van-An Duong ◽  
Jeeyun Ahn ◽  
Na-Young Han ◽  
Jong-Moon Park ◽  
Jeong-Hun Mok ◽  
...  
Keyword(s):  
Diabetic Retinopathy ◽  
Proliferative Diabetic Retinopathy ◽  
Microvascular Complications ◽  
Treatment Options ◽  
Vitreous Body ◽  
Control Group ◽  
Diabetic Patients ◽  
Protein Protein Interaction ◽  
Alpha Beta ◽  
New Treatment

Background: Diabetic Retinopathy (DR), one of the major microvascular complications commonly occurring in diabetic patients, can be classified into Proliferative Diabetic Retinopathy (PDR) and Non-Proliferative Diabetic Retinopathy (NPDR). Currently available therapies are only targeted for later stages of the disease in which some pathologic changes may be irreversible. Thus, there is a need to develop new treatment options for earlier stages of DR through revealing pathological mechanisms of PDR and NPDR. Objective: The purpose of this study was to characterize proteomes of diabetic through quantitative analysis of PDR and NPDR. Methods: Vitreous body was collected from three groups: control (non-diabetes mellitus), NPDR, and PDR. Vitreous proteins were digested to peptide mixtures and analyzed using LC-MS/MS. MaxQuant was used to search against the database and statistical analyses were performed using Perseus. Gene ontology analysis, related-disease identification, and protein-protein interaction were performed using the differential expressed proteins. Results: Twenty proteins were identified as critical in PDR and NPDR. The NPDR group showed different expressions of kininogen-1, serotransferrin, ribonuclease pancreatic, osteopontin, keratin type II cytoskeletal 2 epidermal, and transthyretin. Also, prothrombin, signal transducer and activator of transcription 4, hemoglobin subunit alpha, beta, and delta were particularly up-regulated proteins for PDR group. The up-regulated proteins related to complement and coagulation cascades. Statherin was down-regulated in PDR and NPDR compared with the control group. Transthyretin was the unique protein that increased its abundance in NPDR compared with the PDR and control group. Conclusion: This study confirmed the different expressions of some proteins in PDR and NPDR. Additionally, we revealed uniquely expressed proteins of PDR and NPDR, which would be differential biomarkers: prothrombin, alpha-2-HS-glycoprotein, hemoglobin subunit alpha, beta, and transthyretin.

Effect of Chelated Mineral Mixture on Blood Biochemistry, Hormone and Mineral Status in Repeat Breeder Buffaloes in Tribal Areas of Dahod District in Gujarat, India

2019 ◽  
Vol 15 (01) ◽  
pp. 40-44 ◽  
Author(s):  
P M Joshi ◽  
D Patel ◽  
P D Patel
Keyword(s):  
Treatment Group ◽  
Experimental Period ◽  
Serum Glucose ◽  
Blood Biochemistry ◽  
Control Group ◽  
Blood Collection ◽  
Mineral Status ◽  
Blood Biochemical ◽  
Mineral Mixture ◽  
Repeat Breeder

An on-farm trial for 90 days was conducted at four tribal villages to assess the effect of chelated mineral mixture (CMM) supplementation on blood biochemistry as well as hormonal and mineral status, nutrient intake and reproductive performance of the repeat breeder buffaloes (n = 24). The animals selected were randomly divided into two groups of 12 animals each. The group T1 was control group (farmer’s feeding schedule), and T2 treatment group (T1 + CMM @ 50 g/animal/day). Blood collection was done at 0, 45 and 90 days of the experiment from both the groups for assessment of blood biochemical, hormonal and mineral status of the animals. Average DM, DCP and TDN intake in repeat breeder buffaloes calculated as per information collected from farmers were statistically similar among both the groups and were as per ICAR requirements of animals. Results revealed significant (p less than 0.05) improvement in hemoglobin, serum glucose, total protein, total cholesterol, progesterone, and macro (Ca, P)–micro (Zn, Fe, Cu, Co, Mn) mineral status of chelated mineral supplemented group as compared to control animals. The number of days taken for a successful conception in repeat breeder buffaloes as well as the cost of feeding was also reduced upon supplementation of CMM in T2 as compared to T1 group. The control group recorded a 22.12% higher cost of rearing than the treatment group during the experimental period. The findings revealed the beneficial role of cheated minerals supplementation in improving health, nutritional and reproductive status of repeat breeding buffaloes.

scholarly journals 1186. Cefazolin inoculum effect predicts reduced susceptibility to other antibiotics and patient outcomes in MSSA endovascular infections

2020 ◽  
Vol 7 (Supplement_1) ◽  
pp. S617-S617
Author(s):  
Dan Smelter ◽  
Sue McCrone ◽  
Warren Rose
Keyword(s):  
Infective Endocarditis ◽  
Mortality Rate ◽  
Patient Outcomes ◽  
Treatment Options ◽  
Fold Increase ◽  
Specific Mechanism ◽  
Research Support ◽  
High Burden ◽  
Low Toxicity ◽  
Inoculum Effect

Abstract Background MSSA Infective endocarditis (IE) is inherently a high-burden infection with up to a 30% mortality rate. Cefazolin is an appealing treatment option for IE with low toxicity and a favorable dosing scheme. However, cefazolin has been associated with treatment failure in IE, attributed to an inoculum effect. The specific mechanism underlying the cefazolin inoculum effect (CIE) remains undetermined, but CIE has been linked to both blaZ expression and agr dysfunction. This study aims to determine whether CIE is linked to reduced susceptibility to other antibiotics and worse outcomes regardless of therapy in MSSA endovascular infections. Methods Sixty-four MSSA strains were collected from patients with endovascular infections not treated with cefazolin. To determine CIE phenotype, strains were cultured and MICs assayed for cefazolin, nafcillin, and vancomycin at 107 CFU/mL for high-inocula (HI) and 105 CFU/mL for standard-inocula (SI). This study defined CIE as a ≥ 4-fold increase in MIC at HI compared to SI, with at least an MIC of 4 mg/L at HI. Nitrocefin disks identified blaZ expression, and beta lysin disks were used to determine hemolysin type and agr function. Patient outcomes of mortality and bacteremia duration were assessed across cohorts. Results Twenty-four strains exhibit a CIE (38%), with 10 strains having an MIC of ≥ 32mg/L at HI. Nafcillin and vancomycin also had an inoculum effect, uncoupled from the CIE and occurring at a lower frequency and amplitude at HI. Presence of CIE had a greater association with blaZ expression (71% vs 25%) than agr dysfunction (38% vs 20%). 50% (9/18) of CIE infections were cleared within 48 hours while 77% (20/26) of CIE-negative infections were cleared within 48 hours (P=0.106). However, presence of CIE was not associated with increased mortality (25% CIE-positive vs 35%; P=0.578) Conclusion Previous studies for CIE failed to enrich for isolates from endovascular sources, where inocula are known to be high. This study presents one of the largest endovascular source cohorts for CIE evaluation. It identifies that CIE prevalence (38%) is higher than reports from diverse infection sources (10-36%). CIE appears to predict bacteremia duration with other MSSA treatment options, suggesting mechanisms independent of blaZ and agr function for this phenomenon. Disclosures Warren Rose, PharmD, MPH, Merck (Grant/Research Support)Paratek (Grant/Research Support)

scholarly journals High-fat diet-induced obesity and impairment of brain neurotransmitter pool

2020 ◽  
Vol 11 (1) ◽  
pp. 147-160
Author(s):  
Ranyah Shaker M. Labban ◽  
Hanan Alfawaz ◽  
Ahmed T. Almnaizel ◽  
Wail M. Hassan ◽  
Ramesa Shafi Bhat ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Brain Tissue ◽  
High Fat Diet ◽  
Density Lipoprotein ◽  
Obese Group ◽  
Control Group ◽  
High Fat ◽  
Brain Neurotransmitter ◽  
The Brain ◽  
Lean Group

AbstractObesity and the brain are linked since the brain can control the weight of the body through its neurotransmitters. The aim of the present study was to investigate the effect of high-fat diet (HFD)-induced obesity on brain functioning through the measurement of brain glutamate, dopamine, and serotonin metabolic pools. In the present study, two groups of rats served as subjects. Group 1 was fed a normal diet and named as the lean group. Group 2 was fed an HFD for 4 weeks and named as the obese group. Markers of oxidative stress (malondialdehyde, glutathione, glutathione-s-transferase, and vitamin C), inflammatory cytokines (interleukin [IL]-6 and IL-12), and leptin along with a lipid profile (cholesterol, triglycerides, high-density lipoprotein, and low-density lipoprotein levels) were measured in the serum. Neurotransmitters dopamine, serotonin, and glutamate were measured in brain tissue. Fecal samples were collected for observing changes in gut flora. In brain tissue, significantly high levels of dopamine and glutamate as well as significantly low levels of serotonin were found in the obese group compared to those in the lean group (P > 0.001) and were discussed in relation to the biochemical profile in the serum. It was also noted that the HFD affected bacterial gut composition in comparison to the control group with gram-positive cocci dominance in the control group compared to obese. The results of the present study confirm that obesity is linked to inflammation, oxidative stress, dyslipidemic processes, and altered brain neurotransmitter levels that can cause obesity-related neuropsychiatric complications.

scholarly journals 789. Evaluation of Bezlotoxumab for Prevention of Recurrent Clostridioides difficile Infection in Patients at High Risk for Recurrence

2020 ◽  
Vol 7 (Supplement_1) ◽  
pp. S438-S439
Author(s):  
Tanner M Johnson ◽  
Amanda Howard ◽  
Kerry Schwarz ◽  
Lorna Allen ◽  
Misha Huang ◽  
...  
Keyword(s):  
High Risk ◽  
Fecal Microbiota Transplantation ◽  
Therapeutic Option ◽  
Treatment Options ◽  
High Risk Patient ◽  
Recurrent Infection ◽  
Control Group ◽  
Clostridioides Difficile ◽  
All Cause Mortality ◽  
Clostridioides Difficile Infection

Abstract Background Recurrent Clostridioides difficile infection (rCDI) within 180 days of the index episode is associated with a 33% increase in mortality and, to-date, few treatment options exist to prevent recurrent infection. Bezlotoxumab (BEZ) is a novel therapeutic option for the prevention of rCDI, yet limited data exist regarding its effectiveness in patients at high-risk for recurrence outside of controlled trials. This study aimed to compare BEZ to a historical standard of care (SoC) cohort for the prevention of rCDI in patients at high risk for recurrence. Methods A multi-center retrospective cohort study of patients within an academic health-system with one or more risk factors for rCDI. Patients received SoC with oral vancomycin (VAN) or fidaxomicin (FDX) from January 2015 to December 2017 or BEZ, in addition to oral SoC, from September 2017 to September 2019. The primary outcome was rCDI within 90 days of completion of oral VAN or FDX. Secondary outcomes included all-cause readmission, all-cause mortality, and safety events at 90 days. Results One-hundred twenty patients received BEZ in addition to SoC (n=47) or SoC alone (n=73). Mean (SD) age was 55 (16) years, mean (SD) number of lifetime CDI was 3 (2) episodes, and 30.8% of patients had severe CDI. Six (12.8%) patients in the BEZ cohort and thirty-one (42.5%) in the SoC cohort experienced rCDI at 90 days [OR (95% CI) = 0.20 (0.07-0.53), p=&lt; 0.01]. Incidence of all-cause mortality (2.1% vs 5.5%, p=0.67) and all-cause readmission (42.6% vs 56.2%, p=0.20) within 90 days were not statistically different between groups. Patient body weight, timing of BEZ administration, CDI severity, nor prior receipt of fecal microbiota transplantation significantly affected BEZ effectiveness. BEZ was well tolerated with one infusion-related reaction. There were no heart failure exacerbations among BEZ recipients and two exacerbations identified from control group. Conclusion In patients with at least one risk factor for rCDI, BEZ in addition to SoC was associated with lower rates of recurrent infection than SoC alone and may be a reasonable adjunct therapy in high risk patient populations. Disclosures matthew miller, PharmD, Allergan (Speaker’s Bureau)Tetraphase (Speaker’s Bureau)

scholarly journals RADT-23. IMPACT OF REIRRADIATION UTILIZING STEREOTACTIC RADIOSURGERY ON RECURRENT GLIOBLASTOMA

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii186-ii186
Author(s):  
O’Dell Patrick ◽  
H Nickols ◽  
R LaRocca ◽  
K Sinicrope ◽  
D Sun ◽  
...  
Keyword(s):  
Stereotactic Radiosurgery ◽  
Median Survival ◽  
High Performance ◽  
Performance Status ◽  
Treatment Options ◽  
Methylation Status ◽  
Initial Therapy ◽  
Recurrent Glioblastoma ◽  
Control Group ◽  
The Impact

Abstract BACKGROUND Patients who have recurrent glioblastoma have limited treatment options. We conducted a retrospective review of patients with recurrent glioblastoma treated with standard initial radiation and temozolomide with tumor treating fields to investigate whether reirradiation using radiosurgery would be associated with improved outcomes. METHODS We reviewed the records of 54 consecutively treated patients with recurrent glioblastoma with ECOG 0 or 1 at recurrence and conducted Kaplan-Meier analysis with Log-rank testing to determine significance between groups. RESULTS We identified 24 patients who were treated without radiation therapy (control) while 30 patients underwent re-irradiation using radiosurgery (ReSRS) with a median total dose of 25Gy in five fractions. All patients had completed standard initial therapy, and there was no difference in the time to recurrence between the two groups (10 months for control, 15 months for ReSRS, [P = 0.17, HR for progression 0.65 (95% CI 0.38-1.13)]. A larger proportion of patients in the control arm (54%) had subtotal or gross total resection of the recurrence compared with the ReSRS group (44%, P &lt; 0.05). The majority of patients had recurrence confirmed with biopsy (18/22 in control group, 25/31 in the ReSRS group). MGMT methylation status did not differ between control vs ReSRS (29% vs. 27%). ReSRS was associated with improved median survival from the time of first recurrence of 11.6 months versus 3.8 months in the control arm [P&lt; 0.0001, HR for death 0.33 (95% CI 0.18-0.6)]. CONCLUSIONS In a group of patients with high performance status diagnosed with recurrent glioblastoma, reirradiation with stereotactic radiosurgery was associated with nearly one year median survival after recurrence. Additional analyses are warranted to determine the impact of concurrent systemic therapies with irradiation and underlying tumor or patient factors to predict outcomes.

scholarly journals THU0652-HPR ONLINE EDUCATION YIELDS SIGNIFICANT GAINS IN RHEUMATOLOGISTS’ KNOWLEDGE OF BIOLOGICS AND BIOSIMILARS BUT A SUBSTANTIAL GAP REMAINS

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 570.2-571
Author(s):  
A. Stan ◽  
E. Bell ◽  
P. Schoonheim ◽  
E. Mysler
Keyword(s):  
Online Education ◽  
Statistical Significance ◽  
Treatment Options ◽  
Educational Activity ◽  
Round Table Discussion ◽  
Knowledge Gain ◽  
Regulatory Requirements ◽  
Research Support ◽  
Significance Level ◽  
Post Assessment

Background:Biologics are complex proteins which have revolutionized the treatment of many serious diseases. Due to their complexity and manufacturing which involves living organisms, it is not possible to create identical versions of reference biologics, but it is possible to create biosimilar drugs. Biosimilars have the potential to yield high cost savings and expand treatment options to meet the growing demand for biological therapies.Objectives:This study assessed whether the online CME-accredited round-table-discussion titled “Understanding Biologics: from protein to clinical practice” improved physicians’ understanding of the inherent variability of biologics and what similarity means in the context of biologics as well as the analytical assessment of quality that applies to both biologics and biosimilars.Methods:Rheumatologists participated in an online CME activity (www.medscape.org/viewarticle/900121) consisting of a 30-minute video discussion between 4 experts with accompanying slides. Educational effect was assessed using a 4-question repeated pairs, pre-/post-assessment. A chi-square test was used to determine if a statistically significant improvement (P<.05 significance level) existed in the number of pre-/post-test correct responses. Cramer’s V was used to estimate the level of impact of the education. The CME activity launched on 22 Aug 2018, and the data were collected through 9 Oct 2018.Results:A total of 622 rheumatologists participated in the educational activity, and 87 completed the pre- and postassessment. Overall the activity had a signficiant impact (P<.001) on rheumatologists’ understanding of the inherent variability of biologics and the regulatory requirements for approval of a biosimilar. The Cramer’s V value of 0.186 indicates a considerable effect of the education. The average perecentage of correct responses rose from 33% pre-activity to 51% post-activity. A linked learning assessment (individual responses matched pre- and post-education) showed that 25% of learners improved their knowledge and 26% reinforced their knowledge. The change in percentage of correct responses from pre- to post-assessment achieved statistical significance (P<.05) in 2 of the 3 questions presented: (i) understanding the type of studies needed to demonstrate comparability of a biosimilar to an originator (11% at baseline; 45% post activity), (ii) understanding the type of variability considered acceptable for a biologic (46% at baseline; 63% post activity). However, no knowledge gain was observed regarding basic analytic attributes evaluated to ensure batch to batch consistency (37% at baseline; 38% post activity). Almost 45% of rheumatologists gained confidence in their ability to describe the regulatory requirements for approval of a biosimilar.Conclusion:This online CME activity significantly improved rheumatologists’ understanding of the inherent variability of complex biologic medicines and the role of analytical studies in the regulatory approval of biosimilars. However, there is room for further improving physicians’ knowledge, especially of basic analytics of biologics and biosimilars.Acknowledgments:This CME-certified activity was supported by independent funding from Sandoz.Disclosure of Interests:Adriana Stan Grant/research support from: The CME-certified activity was supported by anindependent educational grant from Sandoz., Elaine Bell: None declared, Peter Schoonheim Grant/research support from: This CME-certified activity was supported by independent funding from Sandoz., Eduardo Mysler Grant/research support from: AbbVie, Lilly, Pfizer, Roche, BMS, Sandoz, Amgen, and Janssen., Consultant of: AbbVie, Lilly, Pfizer, Roche, BMS, Sandoz, Amgen, and Janssen.

Parathyroid hormone promotes cartilage healing after free reduction of mandibular condylar fractures by upregulating Sox9

2021 ◽  
pp. 153537022110271
Author(s):  
Yuanyuan Jia ◽  
Liuqin Xie ◽  
Zhenglong Tang ◽  
Dongxiang Wang ◽  
Yun Hu ◽  
...  
Keyword(s):  
Parathyroid Hormone ◽  
Internal Fixation ◽  
Early Stage ◽  
Rabbit Model ◽  
Mandibular Condyle ◽  
Fracture Site ◽  
Control Group ◽  
Condylar Cartilage ◽  
Cartilage Healing ◽  
Experimental Group

After high fractures of the mandibular condyle, the insufficient blood supply to the condyle often leads to poor bone and cartilage repair ability and poor clinical outcome. Parathyroid hormone (PTH) can promote the bone formation and mineralization of mandibular fracture, but its effects on cartilage healing after the free reduction and internal fixation of high fractures of the mandibular condyle are unknown. In this study, a rabbit model of free reduction and internal fixation of high fractures of the mandibular condyle was established, and the effects and mechanisms of PTH on condylar cartilage healing were explored. Forty-eight specific-pathogen-free (SPF) grade rabbits were randomly divided into two groups. In the experimental group, PTH was injected subcutaneously at 20 µg/kg (PTH (1–34)) every other day, and in the control group, PTH was replaced with 1 ml saline. The healing cartilages were assessed at postoperative days 7, 14, 21, and 28. Observation of gross specimens, hematoxylin eosin staining and Safranin O/fast green staining found that every-other-day subcutaneous injection of PTH at 20 µg/kg promoted healing of condylar cartilage and subchondral osteogenesis in the fracture site. Immunohistochemistry and polymerase chain reaction showed that PTH significantly upregulated the chondrogenic genes Sox9 and Col2a1 in the cartilage fracture site within 7–21 postoperative days in the experimental group than those in the control group, while it downregulated the cartilage inflammation gene matrix metalloproteinase-13 and chondrocyte terminal differentiation gene ColX. In summary, exogenous PTH can stimulate the formation of cartilage matrix by triggering Sox9 expression at the early stage of cartilage healing, and it provides a potential therapeutic protocol for high fractures of the mandibular condyle.

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