Incidence of dislocation and associated risk factors in patients with a femoral neck fracture operated with an uncemented hemiarthroplasty.

BACKGROUND: Several factors might be associated with risk of dislocating following uncemented hemiarthroplasty (HA) due to femoral neck fracture (FNF). Current evidence is limited with great variance in reported incidence of dislocation (1-15%). Aim of this study was to identify the cumulative incidence of first-time dislocation following HA and to identify the associated risk factors. METHOD: We performed a retrospective cohort study of patients receiving an HA (BFX Biomet stem, posterior approach) at Copenhagen University Hospital, Bispebjerg, in 2010-2016. Patients were followed until death or end of study (dec 2018). Dislocation was identified by code extraction from the Danish National Patient Registry. Variables included in the multivariate model were defined pre-analysis to include: age, sex and variables with a p-value < 0.1 in univariate analysis. A regression model was fitted for 90 days dislocation as the assumption of proportional hazard rate (HR) was not met here after. RESULTS: We identified 772 stems (some patients occurred with both right and left hip) and 58 stems suffered 90 dislocations during the observation period, resulting in a 7% (CI 5-9) incidence of dislocation 90 days after index surgery. 55 of the 58 stems (95%) experienced the first dislocation within 90 days after surgery. Only absence of dementia was identified as an independent protective factor in the cause-specific model (HR 0.46 (CI 0.23-0.89)) resulting in a 2.4-fold cumulative risk of experiencing a dislocation in case of dementia. Several other variables such as age, sex, various medical conditions, surgery delay and surgical experience were eliminated as statistical risk factors. We found a decrease in survival probability for patients who experienced a dislocation during follow-up. CONCLUSIONS: The incidence of first-time dislocation of HA (BFX Biomet stem, posterior approach) in patients with a hip fracture is found to be 7% 90 days after surgery. Due to the non-existing attribution bias, we claim it to be the true incidence. Dementia was among several variables identified as the only risk factor for dislocation. In perspective, we may consider treating patients with dementia by other methods than HA e.g., HA with cement or with a more constrained solution. Also, a surgical approach that reduce the risk of dislocation should be considered.

Prediction of drug-drug interactions between roflumilast and CYP3A4/1A2 perpetrators using a physiologically-based pharmacokinetic (PBPK) approach.

This study aimed to develop a physiologically-based pharmacokinetic (PBPK) model to predict changes in the pharmacokinetics (PK) and pharmacodynamics (PD, PDE4 inhibition) of roflumilast (ROF) and ROF N-oxide when co-administered with eight CYP3A4/1A2 perpetrators. The population PBPK model of ROF and ROF N-oxide has been successfully developed and validated based on the four clinical PK studies and five clinical drug-drug interactions (DDIs) studies. In PK simulations, every ratio of prediction to observation for PK parameters fell within the range 0.7 to 1.5. In DDI simulations, except for tow peak concentration ratios (Cmax) of ROF with rifampicin (prediction: 0.63 vs. observation: 0.19) and with cimetidine (prediction: 1.07 vs. observation: 1.85), the remaining predicted ratios closely matched the observed ratios. Additionally, the PBPK model suggested that co-administration with the three perpetrators (cimetidine, enoxacin, and fluconazole) may use with caution, with CYP3A4 strong inhibitor (ketoconazole and itraconazole) or with dual CYP3A41A2 inhibitor (fluvoxamine) may reduce to half-dosage or use with caution, while co-administration with CYP3A4 strong or moderate inducer (rifampicin, efavirenz) should avoid. Overall, the present PBPK model can provide recommendations for adjusting dosing regimens in the presence of DDIs.

Metformin-Cimetidine Drug Interaction and Risk of Lactic Acidosis in Renal Failure: A Pharmacovigilance-Pharmacokinetic Appraisal.

OBJECTIVE: This study aimed to evaluate lactic acidosis (LA) risk when using metformin combined with histamine H2 receptor inhibitors (H2RI) in patients with renal failure (RF). RESEARCH DESIGN AND METHODS: This study analyzed FDA Adverse Event Reporting System data (2012Q4 to 2022Q4) to characterize reports of LA associated with metformin alone or combined with H2RI. Using a disproportionality approach, LA risk signal in the overall population and in patients with RF was assessed. A physiologically based pharmacokinetic (PBPK) model was developed to predict metformin and cimetidine pharmacokinetic changes following conventional doses of the combinations in patients with various degrees of RF. To explore its correlation with LA risk, a peak plasma metformin concentration of 3 mg/L was considered the threshold. RESULTS: Following the 2016 U.S. Food and Drug Administration metformin approval for mild-to-moderate RF, the percentage of patients with RF reporting LA associated with metformin combined with H2RI increased. Disproportionality analysis showed reported LA risk signal associated with metformin and cimetidine in the overall population within the study timeframe only. Furthermore, with PBPK simulations, for metformin (1,000 mg b.i.d.) with cimetidine (300 mg q.i.d. or 400 mg b.i.d.) in stage 1 of chronic kidney disease, metformin (1,000 mg b.i.d.) with cimetidine (300 mg q.i.d. or 400 mg b.i.d. or 800 mg q.d.) in stage 2, and most combinations in stage 3, the peak plasma metformin concentrations exceeded the 3 mg/L threshold. CONCLUSIONS: Metformin combined with cimetidine at conventional doses may cause LA in patients with mild-to-moderate RF.

Identification of Novel and Early Biomarkers for Cisplatin-induced Nephrotoxicity and the Nephroprotective Role of Cimetidine using a Pharmacometabolomic-based Approach Coupled with In Vitro Toxicodynamic Modeling and Simulation.

Cisplatin is widely used for the treatment of various types of cancer. However, cisplatin-induced nephrotoxicity (CIN) is frequently observed in patients receiving cisplatin therapy which poses a challenge in its clinical utility. Currently used clinical biomarkers for CIN are not adequate for early detection of nephrotoxicity, hence there is a need to identify potential early biomarkers in predicting CIN. In the current study, a combination of in vitro toxicodynamic (TD) modeling and untargeted global metabolomics approach was used to identify novel potential metabolite biomarkers for early detection of CIN. In addition, we investigated the protective role of cimetidine (CIM), an inhibitor of the organic cation transporter 2 (OCT2), in suppressing CIN. We first characterized the time-course of nephrotoxic effects of cisplatin (CIS) and the protective effects of CIM in a human pseudo-immortalized renal proximal tubule epithelial cell line (RPTEC), SA7K cell line. Secondly, we used a mathematical cell-level, in vitro TD modeling approach to quantitatively characterize the time-course effects of CIS and CIM as single agents and combination in SA7K cells. Based on the experimental and modeling results, we selected relevant concentrations of CIS and CIM for our metabolomics study. With the help of PCA (Principal Component Analysis) and PLS-DA (Projection to Latent Structure - Discriminate Analysis) analyses, we confirmed global metabolome changes for different groups (CIS, CIM, CIS+CIM vs control) in SA7K cells. Based on the criterion of a p-value ≤ 0.05 and a fold change ≥ 2 or ≤ 0.5, we identified 20 top metabolites that were significantly changed during the early phase i.e. within first 12 h of CIS treatment. Finally, pathway analysis was conducted that revealed the key metabolic pathways that were most impacted in CIN.

Cimetidine for recurrent respiratory papillomatosis in pregnancy as an alternative adjuvant treatment.

BACKGROUND: We report the first case of cimetidine as an alternative adjuvant therapy in a pregnant woman with recurrent respiratory papillomatosis (RRP). A 40 year old woman at 19 week gestation presented with progressive hoarseness and shortness of breath for 1 month. Flexible nasopharyngolaryngoscopy revealed multiple papillomatous lesions over both vocal cords and subglottic area obstructing 60% of her airway. She had previously been diagnosed with juvenile onset RRP at the age of 5 and underwent endoscopic clearance regularly every 6 months. METHOD: The patient was started on a trial of oral cimetidine at a dose of 30 mg/kg and responded well, eventually requiring endoscopic excision only after 2 years. Subsequently, she underwent in vitro fertilisation treatment and stopped taking her cimetidine. After undergoing endoscopic clearance of her papillomata under general anaesthesia, she restarted on cimetidine during her 2nd and 3rd trimester. RESULTS: Ensuing follow-up demonstrated stable minimal papillomata lesions on her right inferior surface of her vocal cord with no recurrence on her left vocal cord and subglottic area. CONCLUSION: Cimetidine is generally safe and not known to be associated with any major teratogenic risks during pregnancy. RRP is postulated to worsen in pregnant women due to the increase in oestrogen levels during pregnancy. Hence, adjuvant therapy was imperative for our patient to reduce recurrent papillomata formation during her pregnancy. Larger scale studies are warranted to assess the use of long-term high-dose cimetidine in terms of efficacy and safety in pregnancy.

Clonidine stimulates force of contraction via histamine H2 receptors in the human atrium.

Clonidine has various clinical effects mediated by agonism of α1- or α2-adrenoceptors and the blocking of hyperpolarization-activated-nucleotide-gated pacemaker channels (HCN). It is unknown whether clonidine can also stimulate human cardiac histamine H2 receptors (hH2Rs). We used isolated electrically stimulated left and spontaneously beating right atrial preparations from mice overexpressing the hH2R specifically in the heart (H2-TG), and spontaneously beating right atrial preparations of guinea pigs for comparison. Moreover, we studied isolated electrically stimulated muscle strips from the human right atrium. Clonidine (1, 3, and 10 µM) increased force of contraction in isolated left atrial preparations from H2-TG mice. In contrast, clonidine reduced the spontaneous beating rate in right atrial preparations from H2-TG. Clonidine raised the beating rate in guinea pig right atrial preparations. Clonidine failed to increase the force of contraction but reduced beating rate in wild-type litter mate mice (WT). In WT, histamine failed to increase the force of contraction in left atrial preparations and beating rate in right atrial preparations. Clonidine (10 µM) increased the force of contraction in isolated human right atrial preparations. The positive inotropic effect in the human atrium was attenuated by cimetidine (10 µM). Clonidine increased the beating rate of the isolated spontaneously beating guinea pig right atrium and acted as a H2R partial agonist. Furthermore, clonidine showed binding to the guinea pig H2R (100 µM) using HEK cells in a recombinant expression system (pKi < 4.5) but hardly to the human H2R. These data suggest that clonidine can functionally activate cardiac human H2R.

Effect of Cimetidine on Metformin Pharmacokinetics and Endogenous Metabolite Levels in Rats.

Tubular secretion is a primary mechanism along with glomerular filtration for renal elimination of drugs and toxicants into urine. Organic cation transporters (OCTs) and multidrug and toxic extrusion (MATE) transporters facilitate the active secretion of cationic substrates, including drugs such as metformin and endogenous cations. We hypothesized that administration of cimetidine, an Oct/Mate inhibitor, will result in increased plasma levels and decreased renal clearance of metformin and endogenous Oct/Mate substrates in rats. A paired rat pharmacokinetic study was carried out in which metformin (5 mg/kg, intravenous) was administered as an exogenous substrate of Oct/Mate transporters to six Sprague-Dawley rats with and without cimetidine (100 mg/kg, intraperitoneal). When co-administered with cimetidine, metformin area under the curve increased significantly by 3.2-fold, and its renal clearance reduced significantly by 73%. Untargeted metabolomics was performed to investigate the effect of cimetidine on endogenous metabolome in the blood and urine samples. Over 8,000 features (metabolites) were detected in the blood, which were shortlisted using optimized criteria, i.e., a significant increase (P value < 0.05) in metabolite peak intensity in the cimetidine-treated group, reproducible retention time, and quality of chromatogram peak. The metabolite hits were classified into three groups that can potentially distinguish inhibition of i) extra-renal uptake transport or catabolism, ii) renal Octs, and iii) renal efflux transporters or metabolite formation. The metabolomics approach identified novel putative endogenous substrates of cationic transporters that could be tested as potential biomarkers to predict Oct/Mate transporter mediated drug-drug interactions in the preclinical stages. SIGNIFICANCE STATEMENT: Endogenous substrates of renal transporters in animal models could be used as potential biomarkers to predict renal drug-drug interactions in early drug development. Here we demonstrated that cimetidine, an inhibitor of organic cation transporters (Oct/Mate), could alter the pharmacokinetics of metformin and endogenous cationic substrates in rats. Several putative endogenous metabolites of Oct/Mate transporters were identified using metabolomics approach, which could be tested as potential transporter biomarkers to predict renal drug-drug interaction of Oct/Mate substrates.

Study of the position of six volar locking plates for distal radius fracture relative to the watershed line.

INTRODUCTION: Volar plate malpositioning in the treatment of distal radial fracture can lead to tendinitis or even tendon tear, especially when the plate position is very distal. We studied the impact of design on plate position in the distal radius. The primary aim was to compare the position of six volar wrist plates relative to the watershed line using the Soong classification. The secondary objectives were to assess the epidemiology of volar locking plate fixation within the administrative Département of Finistère (northwestern France) and to study whether the type of fracture played a role in plate position. HYPOTHESIS: The plate design itself influences positioning relative to the watershed line on the Soong classification. MATERIALS AND METHODS: A total of 2723 volar locking plate fixation cases were analyzed and categorized according to the Soong classification. Plates used were divided into six groups based on design: Zimmer Biomet®, Newclip Technics®, Stryker®, Synthes®, Medartis® and Medartis® Footprint. The number of Soong 0 + 1 plates (i.e., plates graded 0 and 1 taken together) was determined for each design, then compared using the Marascuilo procedure with a significance level of α = 0.05. RESULTS: On the Marascuilo procedure, we found significant differences in the number of Soong grade 0 + 1 plates. The Zimmer Biomet and Newclip Technics® plates were significantly more often proximal to the watershed line than the Synthes and Medartis Footprint plates. Plate position with the Medartis® design was significantly more proximal to the watershed line than for its companion design, the Medartis® Footprint plate. The rate of volar locking plate fixation of distal radial fractures over the past 10 years increased in Finistère. Also, the type of fracture affected the choice of plate when different designs were available within a hospital center (Medartis® Footprint plate used in 2R3A fractures). CONCLUSION: Our study highlights a significant difference in volar locking plate position relative to the watershed line between the various models available. Plate design is a deciding factor when treating distal radial fracture, to avoid impingement when implant removal is not routinely planned.

Influence of Topography and Composition of Commercial Titanium Dental Implants on Cell Adhesion of Human Gingiva-Derived Mesenchymal Stem Cells: An In Vitro Study.

The topography and composition of dental implant surfaces directly impact mesenchymal cell adhesion, proliferation, and differentiation, crucial aspects of achieving osseointegration. However, cell adhesion to biomaterials is considered a key step that drives cell proliferation and differentiation. The aim of this study was to characterize characterize the topography and composition of commercial titanium dental implants manufactured with different surface treatments (two sandblasted/acid-etched (SLA) (INNO Implants, Busan, Republic of Korea; BioHorizonsTM, Oceanside, CA, USA) and two calcium phosphate (CaP) treated (Biounite®, Berazategui, Argentina; Zimmer Biomet, Inc., Warsaw, IN, USA)) and to investigate their influence on the process of cell adhesion in vitro. A smooth surface implant (Zimmer Biomet, Inc.) was used as a control. For that, high-resolution methodologies such as scanning electron microscopy (SEM), X-ray dispersive spectroscopy (EDX), laser scanning confocal microscopy (LSCM), and atomic force microscopy (AFM) were employed. Protein adsorption and retromolar gingival mesenchymal stem cells (GMSCs) adhesion to the implant surfaces were evaluated after 48 h. The adherent cells were examined by SEM and LSCM for morphologic and quantitative analyses. ANOVA and Tukey tests (α = 0.05) were employed to determine statistical significance. SEM revealed that INNO, BioHorizonsTM, and Zimmer implants have an irregular surface, whereas Biounite® has a regular topography consisting of an ordered pattern. EDX confirmed a calcium and phosphate layer on the Biounite® and Zimmer surfaces, and AFM exhibited different roughness parameters. Protein adsorption and cell adhesion were detected on all the implant surfaces studied. However, the Biounite® implant with CaP and regular topography showed the highest protein adsorption capacity and density of adherent GMSCs. Although the Zimmer implant also had a CaP treatment, protein and cell adhesion levels were lower than those observed with Biounite®. Our findings indicated that the surface regularity of the implants is a more determinant factor in the cell adhesion process than the CaP treatment. A regular, nanostructured, hydrophilic, and moderately rough topography generates a higher protein adsorption capacity and thus promotes more efficient cell adhesion.

Erythropoietic protoporphyria: case reports for clinical and therapeutic hints.

BACKGROUND: Erythropoietic protoporphyria is a rare disorder which represents an important health problem in children, causing painful photosensitivity. Little is known on the correlation between genetic profile and clinical manifestations. The standard of care for Erythropoietic protoporphyria is based on avoiding sun and using sun protections, but recent literature has suggested that cimetidine may have a role in improving sun sensitivity. Herein we report our case series describing the successful use of cimetidine and analyzing potential phenotype-genotype correlations. CASE PRESENTATION: This case series describes five patients presented to our Rheumatology Service complaining sun sensitivity. Blood exams and genetic analysis were consistent with the diagnosis of erythropoietic protoporphyria. Four of 5 patients received cimetidine in addition to standard therapies and the effect of treatment was evaluated by Erythropoietic Protoporphyria - Quality of Life questionnaire. CONCLUSIONS: Erythropoietic protoporphyria usually manifests in early childhood after a short sun exposure. Skin manifestations are the main reason for investigations, although sometimes they can be more subtle, leading to a significant diagnostic delay. Skin diseases in children can have profound effects on their family and social relationships. A treatment with cimetidine appears to be an excellent therapeutic option in children with Erythropoietic protoporphyria.

Defining Cephalomedullary Nail Breakage Rates: A Systematic Review and Meta-Analysis.

OBJECTIVE: To establish the background rate of breakage of cephalomedullary nails. DATA SOURCES: MEDLINE, PubMed, and Web of Science were searched on April 3, 2023. STUDY SELECTION: All English-language studies that examined trochanteric with or without subtrochanteric fractures and identified cephalomedullary nail breakage as an outcome measure and a breakage rate could be derived were included. Implants captured were predominantly the TFNA, TFN, and PFN by DePuy Synthes, various versions of the Gamma nail by Stryker, the Zimmer Natural Nail by Zimmer Biomet, and the Intertan by Smith and Nephew. DATA EXTRACTION: The author, year of publication, dates of implant insertion, study design, method of detection of breakages, implant used, number of implant breakages, number of implants inserted, breakage rate, and follow-up were extracted. DATA SYNTHESIS: Meta-analysis of included studies used descriptive nonparametric statistics and a noncomparative proportion for the pooled result. Differences in results between study design types were compared using the mean breakage rate per study design. CONCLUSIONS: Cephalomedullary nail breakage is a rare complication with a median reported rate of 0.6% and a pooled result rate of 0.4%. Ninety-five percent of studies had a breakage rate of 1.3% or less, which sets a benchmark from the reported literature for future studies. There is wide variability in rates of breakage reported between different types of study designs with single-center review studies reporting breakage rates nearly 4-fold greater than large-scale administrative database reviews. The rate of implant breakage should not be used in isolation to judge an implant's performance. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.

Long-term clinical outcomes of the Biomet M2a-38: a retrospective review of 335 total hip arthroplasty cases.

BACKGROUND: At the turn of the century, over one-third of total hip arthroplasties comprised metal-on-metal bearings. As this patient population and their implants age, it is crucial to understand associated late failure modes and expected long-term functional outcomes. We report the long-term results of a large metal-on-metal uncemented total hip arthroplasty system with unique design characteristics compared to others that have been reported with high failure rates. METHODS: We retrospectively analyze our prospective clinical database to determine overall implant survivorship and functional outcomes. Further, we compare these results to the clinical outcomes reported in orthopedic registries and in other published studies with similar metal-on-metal total hip arthroplasty cohorts. RESULTS: Implant survivorship at 10 years was 99.1% and continued to 97.6% survivorship at 20 years. Implant survivorship at 20 years did not vary significantly between sexes (Male: 98.3%, Female: 97.2%; log-rank p-value = 0.46). Mean whole blood cobalt levels were 2.6 µg/L in unilateral cases, 5.3 µg/L in bilateral patients, and 3.4 µg/L for the combined cohort. Average blood chromium levels were 1.4 µg/L in unilateral patients, 2.9 µg/L in bilateral patients, and 1.8 µg/L for group combined. We observed a 0.9% rate of failure due trunnion corrosion at a mean of 13.1 years postoperatively (10.6-15.6 years) but had no bearing wear failures. CONCLUSIONS: Our 20-year implant survivorship of 97.6% with the M2a-38 bearing surpassed registry benchmarks for THA. This large-bearing (38 mm), full hemisphere coverage metal-on-metal system had no bearing wear failures, one failure of instability, one failure of fixation, and three trunnion failures, perhaps suggesting an optimum balance between stability of the joint and the trunnion.

Hypocalcemic tetany associated with simultaneous administration of cimetidine and nifedipine: a case report.

BACKGROUND: Acute hypocalcemia is generally caused by a sudden drop in serum calcium ion and presents with a mild or severe form of tetany. Even though the occurrence of hypocalcemia is well documented with certain drugs such as calcium chelators, bisphosphonates, and cisplatin, it is a very unusual and poorly documented adverse event with cimetidine and nifedipine. Here, we present a case of severe hypocalcemic tetany during simultaneous administration of cimetidine and nifedipine in a hypertensive patient with dyspepsia. CASE PRESENTATION: A 46-year-old known human immunodeficiency virus patient from Ethiopia on antiretroviral therapy over the past 14 years presented to the emergency department with acute exacerbation of dyspepsia and hypertensive urgency. She was given intravenous cimetidine (400 mg) and oral nifedipine (30 mg) simultaneously. One hour after the administration of these two drugs, she developed severe hypocalcemic tetany with carpopedal spasm, involuntary plantar flexion, and muscle spasms. She also had severe retrosternal chest pain and shortness of breath. Her blood pressure was 160/110 mmHg during the attack and she had no skin changes, such as urticaria. She was immediately given 1 g of calcium gluconate intravenously over 30 minutes. The carpopedal spasm progressively decreased during calcium gluconate administration. An hour later, she completely regained voluntary movement of her fingers and feet. The chest pain persisted, but resolved over the next 12 hours. The patient was discharged home after 2 days of observation. This is an unusual adverse effect that needs caution during concomitant administration of these drugs. CONCLUSIONS: Severe hypocalcemic tetany can occur with concomitant administration of cimetidine and nifedipine. Immediate treatment with calcium gluconate quickly reverses this adverse event. Concomitant administration of these drugs should be done with caution or be avoided if possible.

Publication and Career Trends of Ruth Jackson Orthopaedic Society Grant Winners Over the Past Decade.

Background: The Ruth Jackson Orthopaedic Society awards the Jacquelin Perry, MD Resident Research Grant and RJOS/Zimmer Biomet Clinical/Basic Science Research Grant to female orthopedic surgeons, intending to aid women in the progression and completion of their orthopedic research and bolster their pursuit or current career in academic orthopedic surgery. The impact of these grants has not yet been studied. The purpose of this study is to determine the percentage of scholarship/grant-winners who went on to publish the findings of their research, pursue academic positions, and currently hold positions of leadership in the field of orthopedic surgery. Methods: The titles of the winning research projects were searched in PubMed, Embase, and/or Web of Science to ascertain publication status. For each award recipient, the number of publications prior to the award year, number of publications after the award year, total number of publications, and H-index were calculated. Each award recipient was searched online through the websites of their employment and social media pages to determine their residency institution, whether they pursued a fellowship, the number of fellowships they pursued, their subspecialty within orthopedics, their current job, and whether they are in academic or private practice. Results: Of the fifteen Jacquelin Perry, MD Resident Research Grant winners, 73.3% of awarded research projects have since been published. 76.9% of award winners currently work in an academic setting and are affiliated with a residency program, and 0% currently hold leadership positions in orthopedic surgery. Of the eight winners of the RJOS/Zimmer Biomet Clinical/Basic Science Research Grant, 25% have published the findings of their awarded grant. 87.5% of award winners currently work in academics, and 75% hold leadership positions in orthopedic surgery. Conclusion: Our results show that many of the winners of the Jacquelin Perry, MD Resident Research Grant and RJOS/Zimmer Biomet Clinical/ Basic Science Research Grant have published their research findings, continued research within the field of orthopedic surgery, and pursued academic careers and leadership positions. Many of the barriers to career progression and entry into orthopedic surgery that women and underrepresented groups face could be overcome through more grant opportunities and mentorship. Level of Evidence: V.

TNFα-dependent mTOR activity is required for tenotomy-induced ectopic ossification in mice.

INTRODUCTION: Ectopic ossifications often occur in skeletal muscles or tendons following local trauma or internal hemorrhage, and occasionally cause severe pain that limits activities of daily living. However, mechanisms underlying their development remain unknown. MATERIALS AND METHODS: The right Achilles tendon in 8-week-old female or male mice was dissected. Some mice were injected intraperitoneally either with phosphate-buffered saline, dimethyl sulfoxide, cimetidine, rapamycin, celecoxib or loxoprofen for 10 weeks. One week after surgery, immunohistochemical analysis was performed for mTOR, TNFα or F4/80. Ten weeks after surgery, ectopic ossification at the tenotomy site was detected by 3D micro-CT. RESULTS: Ectopic ossification was seen at dissection sites in all wild-type mice by dissection of the Achilles tendon. mTOR activation was detected at dissection sites, and development of ectopic ossification was significantly inhibited by administration of rapamycin, an mTOR inhibitor, to wild-type mice. Moreover, administration of the histamine 2 blocker cimetidine, which reportedly inhibits ectopic ossification in tendons, was not effective in inhibiting ectopic ossification in our models. TNFα-expressing F4/80-positive macrophages accumulate at dissection sites and that ectopic ossification of the Achilles tendon dissection was significantly inhibited in TNFα-deficient mice in vivo. Ectopic ossification is significantly inhibited by administration of either celecoxib or loxoprofen, both anti-inflammatory agents, in wild-type mice. mTOR activation by Achilles tendon tenotomy is inhibited in TNFα-deficient mice. CONCLUSION: The TNFα-mTOR axis could be targeted therapeutically to prevent trauma-induced ectopic ossification in tendons.

P19-derived neuronal cells express H1, H2, and H3 histamine receptors: a biopharmaceutical approach to evaluate antihistamine agents.

Histamine is a biogenic amine implicated in various biological and pathological processes. Convenient cellular models are needed to screen and develop new antihistamine agents. This report aimed to characterize the response of neurons differentiated from mouse P19 embryonal carcinoma cells to histamine treatment, and to investigate the modulation of this response by antihistamine drugs, vegetal diamine oxidase, and catalase. The exposure of P19 neurons to histamine reduced cell viability to 65% maximally. This effect involves specific histamine receptors, since it was prevented by treatment with desloratadine and cimetidine, respectively, H1 and H2 antagonists, but not by the H3 antagonist ciproxifan. RT-PCR analysis showed that P19 neurons express H1 and H2 receptors, and the H3 receptor, although it seemed not involved in the histamine effect on these cells. The H4 receptor was not expressed. H1 and H2 antagonists as well as vegetal diamine oxidase diminished the intracellular Ca2+ mobilization triggered by histamine. The treatment with vegetal diamine oxidase or catalase protected against mortality and a significant reduction of H2O2 level, generated from the cells under the histamine action, was found upon treatments with desloratadine, cimetidine, vegetal diamine oxidase, or catalase. Overall, the results indicate the expression of functional histamine receptors and open the possibility of using P19 neurons as model system to study the roles of histamine and related drugs in neuronal pathogenesis. This model is less expensive to operate and can be easily implemented by current laboratories of analysis and by Contract Research Organizations.

The Clinical Application and Progress of Mirogabalin on Neuropathic Pain as a Novel Selective Gabapentinoids.

Background: Neuropathic pain is a complex sort of pain that is detrimental to individuals' health, both physically and mentally, but merely a small portion of them could witness pain alleviation. Mirogabalin, by distinctive binding characteristics of voltage-gated calcium channels, has won approval from the Japanese authority as a third member of gabapentinoids in Japan. Our review was aimed at encompassing the bulk of clinical research on mirogabalin, which included clinical trials, special considerations, coadministration studies, case reports, and cost-effectiveness studies. Methods: A review was carried out on a series of platforms, such as PubMed, MEDLINE, and Scopus, up to December 2021 using the keywords as follows: "mirogabalin OR mirogabalin besylate OR Tarlige OR DS-5565" AND "neuropathic pain OR Neuropathy." Results: Mirogabalin demonstrated analgesic activity and manageable adverse reactions and provides a new alternative for individuals with PHN or DPNP in 3 phase II and 4 III trials. Mirogabalin alleviated pain markedly in comparison with placebo. Administration of mirogabalin on a long-term basis is a flexible dosage regimen for patients with PHN. It is noteworthy that mirogabalin should be administrated cautiously when combined with probenecid and cimetidine on account of a slight increase in pharmacodynamics effects of mirogabalin. Conclusion: The development of mirogabalin allows further optimization of individual treatment strategies so as to provide more therapeutic choices in this medical domain.

Drug screening in zebrafish larvae reveals inflammation-related modulators of secondary damage after spinal cord injury in mice.

Prolonged inflammation after spinal cord injury is detrimental to recovery. To find pharmacological modulators of the inflammation response, we designed a rapid drug screening paradigm in larval zebrafish followed by testing of hit compounds in a mouse spinal cord injury model. Methods: We used reduced il-1ß linked green fluorescent protein (GFP) reporter gene expression as a read-out for reduced inflammation in a screen of 1081 compounds in larval zebrafish. Hit drugs were tested in a moderate contusion model in mice for cytokine regulation, and improved tissue preservation and locomotor recovery. Results: Three compounds robustly reduced il-1ß expression in zebrafish. Cimetidine, an over-the-counter H2 receptor antagonist, also reduced the number of pro-inflammatory neutrophils and rescued recovery after injury in a zebrafish mutant with prolonged inflammation. Cimetidine action on il-1ß expression levels was abolished by somatic mutation of H2 receptor hrh2b, suggesting specific action. In mice, systemic treatment with Cimetidine led to significantly improved recovery of locomotor behavior as compared to controls, accompanied by decreased neuronal tissue loss and a shift towards a pro-regenerative profile of cytokine gene expression. Conclusion: Our screen revealed H2 receptor signaling as a promising target for future therapeutic interventions in spinal cord injury. This work highlights the usefulness of the zebrafish model for rapid screening of drug libraries to identify therapeutics to treat mammalian spinal cord injury.

Surface Modifications of Commercial Dental Implant Systems: An Overview.

The aim of this review was to perform a comprehensive overview of evidence pertaining to the influence of various surface modifications on the surface roughness, bone implant contact, and the success and complication rates of the implants. Modified sandblasted, large-grit, acid-etched (SLA) implants (SLActive implants) have a higher implant stability quotient compared with conventional SLA implants. Also, when compared between the implant surfaces from various manufacturers, Biomet 3i Nanotite implants were shown to have a relatively higher implant stability quotient compared to Straumann implants as well as the Biomet Osseotite implants. Only one study reports the insertion torque values as obtained by the various implant surfaces, with the findings being statistically similar for all the types, and a higher mean value for Biomet 3i Nanotite implants. Among SLA and SLActive surfaces, the latter was found to have a lower marginal bone loss, and among Astratech implants, the marginal bone loss levels were similar for Osseospeed and Tioblast surfaces. When Osseospeed, TiUnite and SLActive surfaces were compared, Osseospeed was found to have the minimum bone loss while TiUnite was found to have the highest. The bone implant contact percentages are similar and satisfactory for most of the implant surface modifications that are available currently. Upon assessing the recent literature on the survival rates for implants with various surface modifications, it was found that among Nobel Biocare implants, the survival rate was higher for TiUnite implants, compared with the turned surfaces. Surprisingly, among the Straumann implant surfaces, the survival rates were found to be higher for the SLA implants when compared to the modified SLA implants. Only one of the included studies evaluated the survival rate for Astratech implant surfaces and found a 100% survival rate for both the Osseospeed and Tioblast surface implants. Therefore, major advancements have been made in developing novel surfaces of dental implants. The numerous innovations set the stage for rehabilitating patients with high success and predictable survival rates even in challenging conditions.

The Use of a Coded Healing Abutment in the Restoration of a Single, Immediately Placed Implant in the Esthetic Zone: A Clinical Case Report.

For several years, the implant-level impression procedure started by removal of the healing abutment, followed by connection of the impression coping to the implant. Encode Complete (Encode, Biomet 3i, Biomet 3i, Palm Beach Gardens, FL) was introduced to eliminate implant-level impressions by offering a healing abutment-level impression protocol. This report illustrated the treatment of a single tooth in the anterior esthetic zone using Encode Complete. A 23-year-old female patient reported to the prosthodontics clinic complaining of a fractured maxillary anterior tooth that was deemed nonrestorable. After immediate implant placement, soft tissue preservation and temporization of the implant, healing abutment level impression was made. The codes embedded on the occlusal surface communicated the implant depth, hex-orientation, platform diameter, and interface. The definitive Encode gold-plated titanium abutment was anatomically designed virtually with customized margin, contour, taper, and emergence profile. The milling process was initiated, and the virtual design data were sent to the Robocast Center for analog placement in the original Encode master cast. The definitive abutment was placed on the master cast using Robocast technology, followed by the fabrication of the final porcelain fused to zirconia cement-retained all ceramic crown. The abutment was secured to the implant with a Gold-Tite abutment screw, followed by the final cement-retained implant crown placement. Recall visits were obtained at 1 week, 1 month, 3 months, and 1 year after final prosthesis insertion.