A Randomized, Double-Blind, Placebo-Controlled, Multicenter Study to Evaluate the Safety and Efficacy of ThymoQuinone Formula (TQF) for Treating Outpatient SARS-CoV-2.

There is an urgent need for an oral drug for the treatment of mild to moderate outpatient SARS-CoV-2. Our preclinical and clinical study's aim was to determine the safety and preliminary efficacy of oral TQ Formula (TQF), in the treatment of outpatient SARS-CoV-2. In a double-blind, placebo-controlled phase 2 trial, we randomly assigned (1:1 ratio) non-hospitalized, adult (>18 years), symptomatic SARS-CoV-2 patients to receive oral TQF or placebo. The primary endpoints were safety and the median time-to-sustained-clinical-response (SCR). SCR was 6 days in the TQF arm vs. 8 days in the placebo arm (p = 0.77), and 5 days in the TQF arm vs. 7.5 days in the placebo arm in the high-risk cohort, HR 1.55 (95% CI: 0.70, 3.43, p = 0.25). No significant difference was found in the rate of AEs (p = 0.16). TQF led to a significantly faster decline in the total symptom burden (TSB) (p < 0.001), and a significant increase in cytotoxic CD8+ (p = 0.042) and helper CD4+ (p = 0.042) central memory T lymphocytes. TQF exhibited an in vitro inhibitory effect on the entry of five SARS-CoV-2 variants. TQF was well-tolerated. While the median time-to-SCR did not reach statistical significance; it was shorter in the TQF arm and preclinical/clinical signals of TQF activity across multiple endpoints were significant. Therefore, a confirmatory study is planned.

The Role of Puerarin in Chronic Wounds: A Review of its Mechanism of Action and Potential Novel Applications.

Chronic wounds have a high disease burden and significantly influence patient quality of life. The development of chronic wounds is multifactorial and thus adequate management and care is often difficult to achieve. Chronic diseases, malnutrition, smoking, immune dysregulation, and age contribute to chronic wound development. Treatment options include adequately addressing underlying conditions and selecting appropriate topical preparations which enhance and promote healing of different wounds based on an understanding of wound healing pathophysiology. Puerarin, a naturally occurring flavinoid, may offer therapeutic potential for addressing etiologies as well as managing wound beds due to its anti-inflammatory, anti-oxidative, pro-angiogenic, and anesthetic properties.

Chromium and Nickel Concentrations in Subjects with a Stainless Steel Metal-on-Metal Cervical Disc Arthroplasty: Results from a Prospective Longitudinal Study with 7 Years Follow-Up.

BACKGROUND: Cervical disc arthroplasty (CDA) has emerged as an alternative to anterior cervical discectomy and fusion for degenerative cervical disc disease. The artificial discs provide intervertebral motion using multicomponent articulation and thus tend to generate particulate debris and soluble metal ions. Limited information is available on the long-term metal concentrations and associated systemic adverse events observed in metal-on-metal CDA. Serum chromium (Cr) and nickel (Ni) concentrations were assessed in patients implanted with ball-in-trough stainless steel-based cervical disc through 7 years. METHODS: A prospective, nonrandomized longitudinal study was conducted that included 25 patients following rigorous exclusion criteria that included no previous permanent metal implants and no professional exposure to metal particles. Blood serum Cr and Ni concentrations were assayed preoperatively and at 3, 6, 12, 24, 36, 60, and 84 months postoperatively using high-resolution inductively coupled plasma-mass spectrometry. Longitudinal statistical comparisons were made using the Friedman test with statistical significance at P < .05. RESULTS: Median serum concentrations determined preoperatively and at 3, 6, 12, 24, 36, 60, and 84 months postoperatively were 0.074, 0.106, 0.132, 0.170, 0.172, 0.274, 0.192, and 0.203 ng/mL for Cr and 0.085, 0.178, 0.222, 0.175, 0.205, 0.284, 0.181, and 0.194 ng/mL for Ni. The serum Cr concentrations were statistically higher for all postoperative time periods compared to preoperative concentration (Friedman P <.01), whereas serum Ni concentration was statistically higher at the 84-month postoperative time period than the preoperative concentration (Friedman P <.01) and then the concentration at 3, 12, 24, and 60 months postoperatively (Friedman P < .03). CONCLUSIONS: The Cr concentrations detected at all postoperative times were statistically higher than preoperative concentrations, whereas Ni concentration was statistically higher than the preoperative concentration only at 84 months.

Polyetheretherketone (PEEK) Rods for Lumbar Fusion: A Systematic Review and Meta-Analysis.

BACKGROUND: The purpose of this systematic review is to evaluate the safety and effectiveness of polyetheretherketone (PEEK) rod systems in patients receiving lumbar interbody fusion treatment. Meta-analyses of relevant clinical data were also conducted when possible. METHODS: Relevant studies were identified by searching the PubMed, EMBASE, and Cochrane Library databases. Clinical studies evaluating the safety and/or effectiveness of the PEEK rod spinal stabilization system in patients receiving lumbar spinal fusion procedure were included. Studies regarding dynamic stabilization and hybrid stabilization (fixed and dynamic; eg, topping-off technique) were not included in this analysis. The analyses included patients who had a lumbar fusion procedure with PEEK rods or titanium rods as a control reference (only for controlled studies). Fusion success, functional and pain improvement, and safety data were evaluated, if reported. RESULTS: The search yielded 5 studies (1 prospective and 4 retrospectives) that included 177 participants (156 received PEEK rods, and 21 received titanium rods). Meta-analysis of interbody fusion success rate in PEEK rod patients yields the estimate of 95.6% (confidence interval: 91.6% to 98.4%). Functional outcomes in PEEK rod patients demonstrated clinically significant improvement when comparing postoperative to preoperative scores, with an average improvement of 67.4% ± 8.5%. Similarly, pain improvement was clinically significant with an average visual analog scores-back pain and visual analog scores-leg pain improvement percentages of 68.9% ± 8.6% and 76.6% ± 1.5%, respectively. Rod fracture was not reported in any of the studies. The rates of screw fracture and loosening were 3/114 (2.6%) and 1/50 (2.0%), respectively. In the controlled study, no statistically significant difference was reported in the fusion success rate, function improvement, pain improvement, or device-related events between subjects treated with PEEK rods and the subjects treated with titanium rods. CONCLUSIONS: Experience with PEEK rod systems has shown satisfactory clinical outcomes. Therefore, these results support the use of PEEK rod systems as supplemental fixation during lumbar fusion procedures.

Measuring clinically relevant endpoints in a serum-free, three-dimensional, primary cell culture system of human osteoarthritic articular chondrocytes.

Osteoarthritis (OA) is characterized by degeneration of articular cartilage within the joint, inflammation and pain. The purpose of this study was to develop a primary, serum free cell culture system of human osteoarthritic articular chondrocytes (HOACs) with which to study manifestations of the disease process. Joint tissues were obtained from OA patients undergoing total knee arthroplasty (TKA). HOACs isolated from the femoral condyles and tibial plateau of the same side were combined, plated in three-dimensional, alginate beads and cultured for five days in serum, hormone and protein free medium. More living cells were obtained from the femoral condyles than the tibial plateau. The optimal plating density was 2.5 × 106 cells/ml of alginate. The amounts of DNA, RNA, proteoglycans and total collagen were similar in cultures prepared from the sides of least and greatest pathology. More type 1 than type 2 collagen was detected in the medium on days 2 and 5. A greater percentage of type 1 than type 2 collagen was degraded. The inflammatory cytokine interleukin-1 beta was present in the medium and alginate associated matrix. Although variation in the metabolic profiles between subjects was observed, HOACs from all patients continued to reflect the OA phenotype for five days in culture. This serum free, three-dimensional primary culture system of HOACs provides a platform with which to measure clinically relevant endpoints of OA and screen potential disease modifying OA therapeutics.

Heterotopic ossification following single-level anterior cervical discectomy and fusion: results from the prospective, multicenter, historically controlled trial comparing allograft to an optimized dose of rhBMP-2.

OBJECTIVE Heterotopic ossification (HO) has been reported following total hip, knee, cervical, and lumbar arthroplasty, as well as following posterolateral lumbar fusion using recombinant human bone morphogenetic protein-2 (rhBMP-2). Data regarding HO following anterior cervical discectomy and fusion (ACDF) with rhBMP-2 are sparse. A subanalysis was done of the prospective, multicenter, investigational device exemption trial that compared rhBMP-2 on an absorbable collagen sponge (ACS) versus allograft in ACDF for patients with symptomatic single-level cervical degenerative disc disease. METHODS To assess differences in types of HO observed in the treatment groups and effects of HO on functional and efficacy outcomes, clinical outcomes from previous disc replacement studies were compared between patients who received rhBMP-2/ACS versus allograft. Rate, location, grade, and size of ossifications were assessed preoperatively and at 24 months, and correlated with clinical outcomes. RESULTS Heterotopic ossification was primarily anterior in both groups. Preoperatively in both groups, and including osteophytes in the target regions, HO rates were high at 40.9% and 36.9% for the rhBMP-2/ACS and allograft groups, respectively (p = 0.350). At 24 months, the rate of HO in the rhBMP-2/ACS group was higher than in the allograft group (78.6% vs 59.2%, respectively; p < 0.001). At 24 months, the rate of superior-anterior adjacent-level Park Grade 3 HO was 4.2% in both groups, whereas the rate of Park Grade 2 HO was 19.0% in the rhBMP-2/ACS group compared with 9.8% in the allograft group. At 24 months, the rate of inferior-anterior adjacent-level Park Grade 2/3 HO was 11.9% in the rhBMP-2/ACS group compared with 5.9% in the allograft group. At 24 months, HO rates at the target implant level were similar (p = 0.963). At 24 months, the mean length and anteroposterior diameter of HO were significantly greater in the rhBMP-2/ACS group compared with the allograft group (p = 0.033 and 0.012, respectively). Regarding clinical correlation, at 24 months in both groups, Park Grade 3 HO at superior adjacent-level disc spaces significantly reduced range of motion, more so in the rhBMP-2/ACS group. At 24 months, HO negatively affected Neck Disability Index scores (excluding neck/arm pain scores), neurological status, and overall success in patients in the rhBMP-2/ACS group, but not in patients in the allograft group. CONCLUSIONS Implantation of rhBMP-2/ACS at 1.5 mg/ml with polyetheretherketone spacer and titanium plate is effective in inducing fusion and improving pain and function in patients undergoing ACDF for symptomatic single-level cervical degenerative disc disease. At 24 months, the rate and dimensions (length and anteroposterior diameter) of HO were higher in the rhBMP-2/ACS group. At 24 months, range of motion was reduced, with Park Grade 3 HO in both treatment groups. The impact of Park Grades 2 and 3 HO on Neck Disability Index success, neurological status, and overall success was not consistent among the treatment groups. The study data may offer a deeper understanding of HO after ACDF and may pave the way for improved device designs. Clinical trial registration no.: IDE# G060021; data compared with pooled data from control arms of IDE# G010188/NCT00642876 and IDE# G000123/NCT00437190 ( www.clinicaltrials.gov ).

Preoperative intravitreal bevacizumab use as an adjuvant to diabetic vitrectomy: histopathologic findings and clinical implications.

PURPOSE: To evaluate the effects of intervals between preoperative intravitreal injection of bevacizumab (IVB) and surgery on the components of removed diabetic fibrovascular proliferative membranes. DESIGN: Interventional, consecutive, prospective, comparative case series. PARTICIPANTS: A total of 52 eyes of 49 patients with active diabetic fibrovascular proliferation with complications necessitating vitrectomy. METHODS: Participant eyes that had IVB were divided into 8 groups in which vitreoretinal surgery was performed at days 1, 3, 5, 7, 10, 15, 20, and 30 postinjection. A group of eyes with the same diagnosis and surgical intervention without IVB injection was used for comparison. In all eyes, proliferative membrane specimens obtained during vitrectomy were sent for histopathologic examination using hematoxylin-eosin stain, immunohistochemistry (CD34 and smooth muscle actin), and Masson's trichrome stain. MAIN OUTCOME MEASURES: Comparative analysis of different components of the fibrovascular proliferation (CD34, smooth muscle actin, and collagen) among the study groups. RESULTS: Pan-endothelial marker CD34 expression levels starting from day 5 postinjection were significantly less than in the control group (P < 0.001), with minimum expression (1+) in all specimens removed at or after day 30 postinjection. Positive staining for smooth muscle actin was barely detected in the control eyes at day 1, and consistently intense at day 15 and beyond (P < 0.001). The expression level of trichrome staining was significantly high at day 10, compared with control eyes (P < 0.001), and continued to increase at subsequent surgical time points. CONCLUSIONS: A profibrotic switch was observed in diabetic fibrovascular proliferation after IVB, and our results suggest that at approximately 10 days post-IVB the vascular component of proliferation is markedly reduced, whereas the contractile components (smooth muscle actin and collagen) are not yet abundant.

Simultaneous injection of autologous mononuclear cells with TACE in HCC patients; preliminary study.

BACKGROUND: The discovery of the pluripotent stem cells made the prospect of cell therapy and tissue regeneration a clinical reality, especially with the evidence of contribution of the stem cells of bone marrow origin in hepatic regeneration. Infusion of bone marrow stem cells before trans-arterial chemoembolization may help to increase liver volume and consequently increase hepatic reserve in patients with HCC, and this may improve the outcome of this procedure. MATERIALS AND METHODS: Four Child B class patients with unresectable hepatocellular carcinoma treated by transarterial chemoembolization were injected with autologous bone marrow mononuclear layer containing stem cell in the hepatic artery feeding the contralateral lobe of the liver in the same session, follow-up of the patients was done by doing liver profile and CT liver volumetry before the surgery and 3 months later. RESULTS: We observed that patients receiving stem cell therapy simultaneously with TACE had shown a significant improvement in biological and volumetric parameters of liver function compared to those historically reported of patients receiving TACE only who usually shows deterioration of liver parameters. CONCLUSION: BMC infusion into the hepatic artery synchronized with TACE for patients with chronic liver disease complicated with HCC is safe, feasible, and demonstrated an improvement in both biological and radiological volumetric parameters.

Migration of human umbilical cord blood cells into rat liver.

BACKGROUND AND OBJECTIVES: Cell therapy provides an effective strategy for the treatment of an impaired liver. Human umbilical cord blood progenitor cells have the potential to differentiate into hepatocytes. Progenitor cells transplanted into the spleen could migrate directly into the liver through portal circulation. To track migration of human umbilical cord blood progenitor cells in cirrhotic rat liver after intrasplenic transplantation and to prove the possibility similar behavior of human umbilical cord blood nucleated cells in humans. METHODS AND RESULTS: Umbilical cord blood samples from full-term deliveries will be collected after obtaining an informed consent from the mother. The collection procedure will be conducted after completion of delivery and will not interfere with the normal obstetric procedures. Adult male Sprague Dawley rats were subjected to liver cirrhosis by intraperitoneal injection of thioacetamide. Cirrhotic rats were treated with human umbilical cord blood nucleated cells by intra-splenic transplantation. Migration of intrasplenic transplanted human umbilical cord blood cells to the liver was successfully documented with Immunohistochemistry. The liver and spleen from recipient animals were removed. Histopathological and immunohistochemical analysis were performed 20 weeks after intrasplenic injection of the cells. Intrasplenically injected cells migrate to the liver of recipient animals. CONCLUSIONS: Human cord blood nucleated cells have the potential to differentiate into hepatocytes and substantially improve the histology and function of the cirrhotic liver in rats. Relocation into liver after intrasplenic transplantation could be detected by immunohistochemistry. Transdifferentiated cells could be efficiently stained with antihuman hepatocytes.

Stem cell therapy improves the outcome of liver resection in cirrhotics.

INTRODUCTION: Significant proportions of liver cirrhotic patients develop hepatocellular carcinoma and have to undergo hepatic resection. The compromised cirrhotic liver cannot withstand further removal of hepatic tissue, thus, leading to postoperative complication and death. METHODS: In this study, we enrolled 20 patients having liver cirrhosis with hepatocellular carcinoma and randomly assigned them into two groups to receive autologous stem cells or placebo. RESULTS: After 3 weeks, all participants underwent liver resection and were followed for 12 weeks postoperative. We observed that the group receiving preoperative stem cell therapy had shown a significant improvement in all parameters of liver function and had no postoperative complications compared to the group treated with placebo, which showed no improvement in liver parameters and had postoperative complications. DISCUSSION: In conclusion, autologous stem cell therapy can improve the surgical outcome in cirrhotic livers and should be considered as an adjuvant treatment in such patients undergoing hepatic resection.

Cutaneous metastasis of uterine adenocarcinoma: a case report and review of the literature.

Cutaneous metastases from cancer are relatively uncommon in clinical practice but when present may herald the diagnosis of internal malignancy. The most common sources of primary cancer are the breasts, lungs, large bowel, oral cavity, kidneys, stomach, ovaries, and malignant melanoma. Despite the high incidence of uterine adenocarcinoma, cutaneous metastases are uncommon. The most common presentation of cutaneous metastases is rapidly developing nodules or tumors. The diagnosis of cutaneous metastatic carcinoma hinges on histopathologic evaluation of the involved skin. We discuss and review the diagnosis and management of cutaneous metastasis of uterine adenocarcinoma.

Use of human amniotic stem cells for common bile duct reconstruction: vascularized support of a free amnion graft.

BACKGROUND: Benign bile duct stricture is common in surgical practice. The complications of late stricture formation and biliary sepsis still occur in bile duct reconstruction. Many biological and artificial materials have been used to replace the damaged bile duct to avoid bilio-enteric anastomosis, which bypasses the biliary sphincter mechanism. Amniotic epithelial (AE) cells are known to have unique characteristics, such as low-level expression of major histocompatibility complex antigens and a less restricted differentiation potential. AE cells differentiate into different cell types from all three germ layers, including cardiomyocytic, myocytic, osteocytic, adipocytic (mesodermal), pancreatic, hepatic (endodermal), neural, and astrocytic (neuroectodermal) cells in vitro, suggesting a promising candidate to reconstruct the damaged bile duct. MATERIAL/METHODS: Human amniotic grafts (as a source of stem cells) with or without vascularized peritoneomuscular flap were used to repair damaged bile ducts (non-circumferential and circumferential bile duct loss) in a dog model. RESULTS: Non-circumferential bile duct loss appeared to be satisfactorily repaired using amnion graft alone. However, circumferential duct loss was not adequately repaired with amnion graft alone, but it was adequately repaired using amnion graft with a vascularized peritoneomuscular flap. In adequately repaired cases, histological examination demonstrated that the biliary mucosal endothelium had grown over the amniotic membrane graft. CONCLUSIONS: Collectively, the data presented here suggest that the use of human amnion as a source of amniotic stem cells provides a very promising tool for tissue reconstruction.

Osteoactivin bioinformatic analysis: prediction of novel functions, structural features, and modes of action.

BACKGROUND: The initial identification of osteoactivin (OA) came from studies using an animal model of osteopetrosis in rats. Several recent studies suggested roles for OA in osteoblast differentiation, fibroblast differentiation, cancer metastasis, and attenuation of muscle, liver, and kidney injury-induced degeneration. MATERIAL/METHODS: Several bioinformatic tools were utilized, including ArrayExpress, Pfam, SMART, Prosite, ELM, ProFun, PFP, Consensus Secondary Structure Prediction server, and Geno3D. RESULTS: 1) Novel OA functions and biological roles were predicted, including roles in cell envelope formation, enzyme activities, immune response activities, negative regulation of B-cell activation, antigen processing, heme catabolism, endothelial cell differentiation, establishment of protein localization, melanin biosynthesis from tyrosine, regulation of blood pressure, response to light, and lung development. 2) Novel OA functional motifs were predicted, including N-Arg dibasic convertase cleavage site, NEC1/NEC2 cleavage site, peptide C-terminal amidation, glycosaminoglycan attachment site, and generic motif for N-glycosylation, and substrate recognition sites that interact with different cytosolic proteins, including cyclin, MAPK, Class III PDZ domains, GSK3, phosphorylase kinase, tyrosine-based sorting signal, and internalization signal. 3) OA's secondary and tertiary structural models were predicted. CONCLUSIONS: bioinformatic structural analysis predicted that OA has three major structural domains: two helical structures on its termini and beta sheets as a sandwich-like structure in the middle. Several functional motifs have been predicted suggesting different modes for OA functions (receptor, ligand, and enzyme). Combined data from OA's expression array and function prediction data suggest that OA might play a role in several pathologic conditions, including hypertension, diabetes, and immune system disorders.

Melanotic neuroectodermal tumor of infancy: review of literature and case report.

Melanotic neuroectodermal tumor of infancy (MNTI) is an uncommon, fast-growing, pigmented neoplasm of neural crest origin. It primarily affects the maxilla of the infants during the first year of life. Approximately, a few hundred of these tumors have been reported in medical literature. We present a case of a newborn with MNTI involving the anterior maxillary region. The treatment included surgical excision of the lesion with safe margins, using an intraoral approach and removal of associated developing tooth buds. We made no attempt at immediate bone grafting. The patient had no recurrence at 1 year postoperatively. The diagnostic features and management alternatives of MNTI are discussed.

The role of osteoactivin-derived peptides in osteoblast differentiation.

BACKGROUND: In our previous studies, we found that osteoactivin (OA) plays an important role in the regulation of osteoblast differentiation in vitro. Our studies also suggested that the region of OA protein that contains an RGD motif might play a vital role in the function of OA in osteoblast differentiation. In this study, we examined the functional role of OA-derived peptide containing the RGD motif (OA-D) in osteoblast differentiation. MATERIAL/METHODS: For this purpose, we designed another peptide, termed OA-E, that has sequence similar to OA-D but with glutamic acid (E) instead of aspartic acid (D). The effect of OA-E peptide on osteoblast differentiation was examined. Interestingly, OA-E peptide induced osteoblast differentiation in a manner similar to OA-D peptide. These data suggested that the effect of OA-derived peptides is RGD independent and it could be dependent on other features in the amino acid sequence of these peptides. RESULTS: OA-D peptide treatment markedly induced osteoblast differentiation markers in vitro compared to cultures treated with negative control peptide (NCP). Interestingly, OA-E peptide induced osteoblast differentiation in a manner similar to OA-D peptide. These data suggested that the effect of OA-derived peptides is RGD independent and it could be dependent on other features in the amino acid sequence of these peptides. Since phosphorylation of amino acid residues in proteins and peptides plays a major role in biological systems, the phosphorylation pattern of amino acid sequences of OA-derived peptides and OA protein family members were examined using bioinformatic analysis tools. We found that OA-derived peptides and OA protein family members have serine residue, close to c-terminus and might be phosphorylated with casein kinase II. Casein kinase II is known to phosphorylate many osteoblast-related proteins that regulate osteoblast development and differentiation such as osteopontin and vitronectin. CONCLUSIONS: Collectively, these data showed that both OA-D and OA-E peptides significantly induced osteoblast differentiation in vitro and that effect is RGD independent.

Use of sclerosing agent in the management of oral and perioral hemangiomas: review and case reports.

BACKGROUND: Most cutaneous hemangiomas involute spontaneously. However, the lesion existing on the face poses a cosmetic problem while waiting for involution. CASE REPORTS: Three hemangioma cases were treated by repeated local injection of 5% ethanolamine oleate solution. The lesions flattened and markedly reduced in size as shown by clinical and imaging evaluation. CONCLUSIONS: Use of 5% ethanolamine oleate as a sclerosing agent for repeated intralesional injection in the management of facial hemangiomas is a safe treatment with acceptable results. As presented here, this technique offers the patient considerable relief of symptoms with minimal complications. However, the possibility of second-stage surgery to correct residual deformity is still considered. Sclerotherapy with ethanolamine oleate provides a good preparation for further surgery.

Sporadic and syndromic keratoacanthomas: diagnosis and management.

Keratoacanthomas are neoplasms of the skin and mucous membranes. Their nature continues to fuel controversies about the benign versus malignant nature of these tumors. The characteristics of keratoacanthomas (both the sporadic and syndromic types), the controversies about the benign versus malignant nature of keratoacanthomas, and current treatment options for keratoacanthomas are discussed.