A synthetic bioactive peptide of the C-terminal fragment of adhesion protein Fibulin7 attenuates the inflammatory functions of innate immune cells in LPS-induced systemic inflammation.

OBJECTIVE: Systemic inflammation is associated with improper localization of hyperactive neutrophils and monocytes in visceral organs. Previously, a C-terminal fragment of adhesion protein Fibulin7 (Fbln7-C) was shown to regulate innate immune functionality during inflammation. Recently, a shorter bioactive peptide of Fbln7-C, FC-10, via integrin binding was shown to reduce ocular angiogenesis. However, the role of FC-10 in regulating the neutrophils and monocyte functionality during systemic inflammatory conditions is unknown. The study sought to explore the role of FC-10 peptide on the functionality of innate immune cells during inflammation and endotoxemic mice. METHODS: Neutrophils and monocytes were isolated from healthy donors and septic patient clinical samples and Cell adhesion assay was performed using a UV spectrophotometer. Gene expression studies were performed using qPCR. Protein level expression was measured using ELISA and flow cytometry. ROS assay, and activation markers analysis in vitro, and in vivo were done using flow cytometry. TREATMENT: Cells were stimulated with LPS (100 ng/mL) and studied in the presence of peptides (10 µg, and 20 µg/mL) in vitro. In an in vivo study, mice were administered with LPS (36.8 mg/kg bw) and peptide (20 µg). RESULTS: This study demonstrates that human neutrophils and monocytes adhere to FC-10 via integrin ß1, inhibit spreading, ROS, surface activation markers (CD44, CD69), phosphorylated Src kinase, pro-inflammatory genes, and protein expression, compared to scrambled peptide in cells isolated from healthy donors and clinical sample. In line with the in vitro data, FC-10 (20 µg) administration significantly decreases innate cell infiltration at inflammatory sites, improves survival in endotoxemia animals & reduces the inflammatory properties of neutrophils and monocytes isolated from septic patients. CONCLUSION: FC-10 peptide can regulate neutrophils and monocyte functions and has potential to be used as an immunomodulatory therapeutic in inflammatory diseases.

Incidence of Postoperative Pain After Single- and Multiple-Visit Root Canal Treatment in Patients Reporting in the Conservative Dentistry and Endodontics Outpatient Department of a Tertiary Care Hospital: A Cross-Sectional Study.

This study aimed to conduct a human study to determine the incidence of postobturation pain using different parameters. In this cross-sectional study, 240 patients were included, which were equally allocated into two groups: single visit and multiple visit, 120 in each. Patients in both the single and multiple visits were further categorized into two subgroups, subgroup 1-no occlusal reduction and subgroup 2-occlusion reduction each having 60 patients. Corresponding to the type of visit, patients were followed by the role of medication into two groups, subgroup 1-both analgesics and antibiotics, subgroup 2-only analgesics, and subgroup 3-no medication. Following this approach and the criteria of the study, patients' performa was made, and based on this performa, the intensity of subjective symptoms, particularly postobturation pain, was determined using the visual analog scale (VAS). The data were then analyzed using the Chi-square test. Results were such that a single visit, no occlusal reduction, and only analgesics will be better for patients with irreversible pulpitis as chosen in the present study. Within the limitations of the present study, it can be concluded that single-sitting root canal treatment should be preferred over multiple sitting where there is no periapical inflammation; also, the occlusal reduction could be exempted from the same. To relieve the patient from postoperative pain where complete debridement is possible, antibiotics can be excluded from the regimen and only analgesics could be prescribed.

Comparative evaluation of smear layer removal by using different irrigant activation techniques: An in vitro scanning electron microscopic study.

Aim: This in vitro study aims to assess and compare the effectiveness of different irrigation activation techniques in removing the smear layer from the root canal dentin using Scanning electron microscope (SEM) analysis. Materials and Methods: A total of 60 extracted single-rooted premolar with straight canal and mature apex were used for this study. After the selection of teeth, all the samples were decoronated followed by biomechanical preparation. The sample after preparation was irrigated with sodium hypochlorite and randomly divided into three groups with 20 sample in each group (n = 20), (Group 1) control, (Group 2) ultrasonic, and (Group 3) laser. The irrigant activation was done in all the groups and then sample was prepared for the scanning electron microscope analysis. Statistical Analysis: The statistical analysis was performed using the Mann-Whitney-U-test. Results: The findings suggested that the diode laser irrigant activation technique was superior to the ultrasonic and conventional techniques to eradicate smear layers. Conclusion: With the limitation of this study, diode laser activation showed better cleaning of root dentinal walls compared to ultrasonic activator and traditional method.

Monocytes and macrophages: Origin, homing, differentiation, and functionality during inflammation.

Monocytes and macrophages are essential components of innate immune system and have versatile roles in homeostasis and immunity. These phenotypically distinguishable mononuclear phagocytes play distinct roles in different stages, contributing to the pathophysiology in various forms making them a potentially attractive therapeutic target in inflammatory conditions. Several pieces of evidence have supported the role of different cell surface receptors expressed on these cells and their downstream signaling molecules in initiating and perpetuating the inflammatory response. In this review, we discuss the current understanding of the monocyte and macrophage biology in inflammation, highlighting the role of chemoattractants, inflammasomes, and integrins in the function of monocytes and macrophages during events of inflammation. This review also covers the recent therapeutic interventions targeting these mononuclear phagocytes at the cellular and molecular levels.

Ultrasmall ATP-Coated Gold Nanoparticles Specifically Bind to Non-Hybridized Regions in DNA.

Here we report the synthesis of ultrasmall (2 nm in diameter) ATP-coated gold nanoparticles, ATP-NPs. ATP-NPs can be enlarged in a predictable manner by the surface-catalyzed reduction of gold ions with ascorbate, yielding uniform gold nanoparticles ranging in size from 2 to 5 nm in diameter. Using atomic force microscopy (AFM), we demonstrate that ATP-NPs can efficiently and selectively bind to a short non-hybridized 5A/5A region (composed of a 5A-nucleotide on each strand of the double helix) inserted into a circular double-stranded plasmid, Puc19. Neither small (1.4 nm in diameter) commercially available nanoparticles nor 5 nm citrate-protected ones are capable of binding to the plasmid. The unique ability to specifically target DNA regions characterized by local structural alterations of the double helix can pave the way for applications of the particles in the detection of genomic DNA regions containing mismatches and mutations that are common for cancer cells.

Role of Temporomandibular Total Joint Replacement in Correction of Facial Deformities.

Introduction: Individuals suffering from facial deformities experience esthetic, functional and social setback in their lives every day. These patients benefit greatly with single-stage temporomandibular joint replacement along with orthognathic surgical procedures to correct functional as well as esthetic components. Methodology: Five individuals with facial deformities due to hemifacial macrosomia, fibrous dysplasia, idiopathic condylar resorption, ankylosis, etc., were treated with total joint replacement along with orthognathic surgical procedures for functional and esthetic correction. The customized temporomandibular joint was digitally custom designed, and the orthognathic procedures were virtually planned on NemoFAB software before performing the surgical procedure. Results: Intraoperatively, the overall time was reduced considerably with minimal unpredictable complications. One-week postoperative computed tomographs were obtained and superimposed on preoperative virtual surgical planning which showed minimal discrepancy. Follow-up period of 18-30 months was maintained for all the patients with stable results, minimal relapse and satisfactory functional abilities. Discussion: Total joint replacement along with orthognathic procedure provides single-stage functional and esthetic corrections for the patients, considerably improving their quality of life. Precise preoperative surgical planning proves to be an indispensable step for achieving desired results with minimal margin of error and avoid any unseen complications during the surgical procedure.

Comparative evaluation of the quality and homogeneity of different obturating systems using cone-beam computed tomography - An in vitro study.

Aim: The aim of this study was to evaluate the homogeneity and quality of different obturating systems using cone-beam computed tomography (CBCT). Materials and Methods: One hundred and twenty extracted maxillary and mandibular molars were included in this study which was decoronated first and then dissected into palatal and distal roots. After working length determination, all the roots were biomechanically prepared with ProTaper universal system. The prepared roots were evaluated using CBCT, and volumetric analysis was done. Samples were then randomly divided into three groups corresponding to the obturation method used - cold lateral compaction technique, single-cone technique, and BeeFill 2 in 1 system. After obturation, CBCT imaging and volumetric analyses were performed again to compare and analyze the amount of volume of obturation in different obturating techniques. To standardize the volume, pre-and postobturation images were superimposed. To avoid errors, for each section, measurements were repeated three times and the means were calculated. Statistical Analysis Used: The data were statistically analyzed using one-way analysis of variance, followed by post hoc test. Results: Results showed a statistically significant difference of the single cone with lateral compaction and the BeeFill system (P < 0.001). Maximum volume of obturating material was found in BeeFill at all levels - Coronal, middle, and apical, followed by cold lateral compaction and single-cone technique (P < 0.001). Conclusion: It could be concluded that the thermoplasticized obturating technique can be a better choice for obturation rather than the single cone and lateral compaction technique.

An Abnormal Case of Diabetic Myonecrosis: A Case Report and Review of Literature.

Diabetic myonecrosis, also known as diabetic muscle infarct, is a rare complication of diabetes mellitus, generally associated with poor glycemic control. It is often difficult to diagnose due to its nonspecific presentation and lack of awareness of the complication. Routine laboratory investigations often do not aid in diagnosis. Magnetic resonance imaging (MRI) may assist in diagnosis but is not routinely ordered due to cost-effectiveness and nonspecific radiologic appearance. Muscle biopsy can provide a definite diagnosis; however, it is often avoided due to its invasiveness. Treatment consists of glycemic control, rest, and analgesics for pain control. Our case describes a 42-year-old male with uncontrolled diabetes who presented with four weeks of progressively worsening right-sided lower extremity pain. The patient was taken to the operating room for concern for necrotizing fasciitis; however, it was ultimately ruled out. A diagnosis of diabetic myonecrosis was made. Recommendations were given for strict blood sugar control and to start aspirin 81 mg daily. The patient was later seen in the outpatient clinic with improvement in the lower extremity pain.

An Incidental Finding of Takotsubo Cardiomyopathy in a Trauma Case.

Takotsubo cardiomyopathy (TC) is a transient condition characterized by left ventricular wall motion abnormalities, ventricular systolic dysfunction, and apical ballooning. When initially presented, the pathology is often erroneously attributed to acute coronary syndrome (ACS) or acute-onset heart failure due to similar symptoms and electrocardiogram (ECG) findings. However, upon further review of imaging, coronary arteries are often void of disease. The highest prevalence of Takotsubo cardiomyopathy is noted in elderly, postmenopausal women who recently experienced an emotionally or physically triggering event. Although the true underlying pathophysiology of Takotsubo cardiomyopathy remains poorly elucidated, a few leading concepts suggest that stress-induced sympathetic responses may lead to catecholamine-induced cardiotoxicity. Other ideologies implicate poor coronary perfusion, neurogenic myocardial stunning, and coronary artery vasospasms. As features of TC are transient, it has an excellent prognosis, and patients see improvement in ventricular function and symptoms within weeks after the initiation of therapy. In this paper, we discuss a case of TC noted incidentally on imaging in a middle-aged female presenting with encephalopathy after a motor vehicle accident.

Gender Affirming Surgery in Nonbinary Patients: A Single Institutional Experience.

Background An increasing number of nonbinary patients are receiving gender-affirming procedures due to improved access to care. However, the preferred treatments for nonbinary patients are underdescribed. The purpose of this study was to investigate the goals and treatments of nonbinary patients. Methods A retrospective study of patients who self-identified as nonbinary from our institutional Gender Health Program was conducted. Patient demographics, clinical characteristics, surgical goals, and operative variables were analyzed. Results Of the 375 patients with gender dysphoria, 67 (18%) were nonbinary. Over half of the nonbinary patients were assigned male at birth ( n = 57, 85%) and nearly half preferred the gender pronoun they/them/theirs ( n = 33, 49%). A total of 44 patients (66%) received hormone therapy for an average of 2.5 ± 3.6 years, primarily estrogen ( n = 39). Most patients ( n = 46, 69%) received or are interested in gender-affirming surgery, of which, almost half were previously on hormone therapy ( n = 32, 48%). The most common surgeries completed or desired were facial feminization surgery ( n = 15, 22%), vaginoplasty ( n = 15, 22%), mastectomy ( n = 11, 16%), and orchiectomy ( n = 9, 13%). Nonbinary patients who were assigned male at birth (NB-AMAB) were more often treated with hormones compared to nonbinary patients assigned female at birth (NB-AFAB) (72% vs. 30%, p = 0.010). Conversely, patients who were AFAB were more likely to complete or desire surgical intervention than those who were AMAB (100% vs. 63.0%, p < 0.021). Conclusion Majority of nonbinary patients were assigned male at birth. NB-AFAB patients all underwent surgical treatment, whereas NB-AMAB patients were predominantly treated with hormone therapy.

A Novel Method to Rehabilitate Post-mucormycosis Maxillectomy Defect by Using Patient-Specific Zygoma Implant.

Aim: During second wave of COVID pandemic, India faced heavy surge of mucormycosis. Treatment option for these patients included either total or partial maxillectomy with primary closure. Rehabilitation of these patients became challenging because of their age and size of defect. The purpose of the present study is to present a new digital technique for the fabrication of patient-specific zygoma implants (PSI) and to report on its survival and complication rates. Material and Methods: Total 21 patients who had undergone either partial or total maxillectomy after mucormycosis and who were disease-free clinically and radiographically for 6 or more months post-resection were rehabilitated using patient-specific zygoma implant. CT scan was obtained for all patients post-maxillectomy for evaluation of existing bone condition. Exocad software was used for virtual surgical planning of zygoma implant considering surgical and prosthetic technicality to achieve goal of maximum functionality and sustainability. Result: All the patients were followed up after 15, 30, 45 and 90 days and there after every month for evaluation of soft tissue healing, infection, dehiscence, loosening of prosthesis, eating efficiency and aesthetic. Follow-up period for all 15 patients was in the range of 6-12 months. Conclusion: In case of post-mucor maxillectomy patients, use of PSI offers the advantages of minimal bone augmentation, reduction in time required to restore lost function, and reduced financial burden of multiple procedures. Therefore, PSI may represent a valid alternative treatment for the prosthetic restoration of post-mucor maxillectomy patients.

Small cell neuroendocrine carcinoma with primary orbital involvement - The unseen, and a review of literature.

Neuroendocrine neoplasms are derived from the epithelial lineages mainly of respiratory tract, with predominant neuroendocrine differentiation. There are only a handful of documented cases of paranasal small cell neuroendocrine carcinomas (SNEC) with primary orbital involvement. Here, the authors describe a 33-year-old male patient with rapidly progressive swelling of the right lower lid with proptosis since 4 weeks. On contrast-MRI orbit, an ill-defined multilobulated mass measuring 3.6 × 3.1 cm with intense homogenous enhancement was seen in the right retrobulbar space involving the right ethmoid sinus. On incisional biopsy, a poorly differentiated mass containing numerous small round blue cells and scanty intervening stroma with prominent necrosis and apoptosis was seen. Immunohistochemistry was strongly positive for synaptophysin. He was diagnosed as a case of SNEC and received chemotherapy, with good response till date of 9 months of follow up. The authors present a literature review and describe challenges in management of a primary orbital SNEC.

Inflammation driven metabolic regulation and adaptation in macrophages.

Macrophages are a diverse population of phagocytic immune cells involved in the host defense mechanisms and regulation of homeostasis. Usually, macrophages maintain healthy functioning at the cellular level, but external perturbation in their balanced functions can lead to acute and chronic disease conditions. By sensing the cues from the tissue microenvironment, these phagocytes adopt a plethora of phenotypes, such as inflammatory or M1 to anti-inflammatory (immunosuppressive) or M2 subtypes, to fulfill their spectral range of functions. The existing evidence in the literature supports that in macrophages, regulation of metabolic switches and metabolic adaptations are associated with their functional behaviors under various physiological and pathological conditions. Since these macrophages play a crucial role in many disorders, therefore it is necessary to understand their heterogeneity and metabolic reprogramming. Consequently, these macrophages have also emerged as a promising target for diseases in which their role is crucial in driving the disease pathology and outcome (e.g., Cancers). In this review, we discuss the recent findings that link many metabolites with macrophage functions and highlight how this metabolic reprogramming can improve our understanding of cellular malfunction in the macrophages during inflammatory disorders. A systematic analysis of the interconnecting crosstalk between metabolic pathways with macrophages should inform the selection of immunomodulatory therapies for inflammatory diseases.

From Diagnosis to Treatment: Exploring the Latest Management Trends in Cervical Intraepithelial Neoplasia.

Cervical intraepithelial neoplasia (CIN) stands as a precancerous condition with the potential to progress to invasive cervical cancer. This comprehensive review explores the intricacies of CIN management, beginning with its definition, classification, and etiology. It emphasizes the significance of early detection and outlines the latest trends in diagnosis, including Pap smears, human papillomavirus (HPV) testing, and colposcopy. Grading and staging, pivotal in treatment selection, are elucidated. Current management approaches, encompassing watchful waiting, surgical interventions, emerging minimally invasive techniques, and immunotherapy, are detailed. The factors influencing treatment decisions, informed consent, and patient education are discussed. Potential complications following treatment, the importance of long-term follow-up, and the role of HPV vaccination in prevention are underscored. Finally, the review looks to the future, discussing advances in detection, novel treatments, and the promise of precision medicine. In conclusion, early detection and management remain the cornerstone of CIN care, offering hope for a future where cervical cancer is a preventable and treatable condition.

Postpartum Depression and Its Biological Biomarkers.

A woman's life is significantly impacted by both pregnancy and childbirth. A woman's tasks and obligations undergo abrupt and significant adjustments as a result of having a child. As a result, the postpartum period is when a new mother is most likely to develop postpartum depression. It frequently has serious detrimental effects on the infant. Similar signs and risk factors can also be seen in non-postpartum depression. The main difference is that postpartum-specific factors, including biological and psychosocial ones, are what lead to postpartum depression. Among biological processes, inflammatory processes and hypothalamic-pituitary-adrenal dysfunction are the best indicators of postpartum depression risk. Many biomarkers have also been discovered using the cutting-edge multi-omics approach. Psychotherapy and antidepressants are frequently used to treat postpartum depression, although there has been much worry about the drugs' potential negative effects, such as decreased appetite, dizziness, headaches, and drowsiness. To prevent the negative effects of postpartum depression on both mother and child, it is crucial to correctly identify and treat it during the postnatal period as soon as feasible.

A Clinical Re-Evaluation of an Unexplored Technique for Post Gap Arthroplasty Retrognathic Mandible.

Aims: The current manuscript explores the viability of reverse sagittal split osteotomy technique for correction of ankylotic cases with post gap arthroplasty mandibular retrognathia to achieve socially acceptable esthetic results. Method: Reverse sagittal split osteotomy which was introduced by Collins et al in 1983 was performed with certain modifications on two cases to correct mandibular hypoplasia in post gap arthroplasty cases. The paper also highlights intraoral as well as extraoral approach for performing the osteotomy along with better management of bad split under direct vision. Result: It was observed that the reverse sagittal split technique for advancement of mandible in cases of tmj ankylosis-induced dentofacial deformity provided better proximal control, reduced chances of bad split, greater range of advancement (11-14 mm) with esthetically acceptable results. The osteotomy cuts on lateral surface of mandible make the procedure effectively easier and quicker with better control over proximal segment and management under direct vision. Conclusion: When Distraction Osteogenesis and conventional orthognathic is not a choice in management of dentofacial deformity of post-release ankylosis cases due to the poor proximal control and concern over bad split, reverse sagittal split can be an appropriate choice to manage these deformities without any donor site morbidity.

Reengineering Ponatinib to Minimize Cardiovascular Toxicity.

Small molecule tyrosine kinase inhibitors (TKI) have revolutionized cancer treatment and greatly improved patient survival. However, life-threatening cardiotoxicity of many TKIs has become a major concern. Ponatinib (ICLUSIG) was developed as an inhibitor of the BCR-ABL oncogene and is among the most cardiotoxic of TKIs. Consequently, use of ponatinib is restricted to the treatment of tumors carrying T315I-mutated BCR-ABL, which occurs in chronic myeloid leukemia (CML) and confers resistance to first- and second-generation inhibitors such as imatinib and nilotinib. Through parallel screening of cardiovascular toxicity and antitumor efficacy assays, we engineered safer analogs of ponatinib that retained potency against T315I BCR-ABL kinase activity and suppressed T315I mutant CML tumor growth. The new compounds were substantially less toxic in human cardiac vasculogenesis and cardiomyocyte contractility assays in vitro. The compounds showed a larger therapeutic window in vivo, leading to regression of human T315I mutant CML xenografts without cardiotoxicity. Comparison of the kinase inhibition profiles of ponatinib and the new compounds suggested that ponatinib cardiotoxicity is mediated by a few kinases, some of which were previously unassociated with cardiovascular disease. Overall, the study develops an approach using complex phenotypic assays to reduce the high risk of cardiovascular toxicity that is prevalent among small molecule oncology therapeutics. SIGNIFICANCE: Newly developed ponatinib analogs retain antitumor efficacy but elicit significantly decreased cardiotoxicity, representing a therapeutic opportunity for safer CML treatment.

Orbital Aspergillosis, a great masquerader: a series of three unusual cases and a review of the literature.

Fungal infections of the orbit are infrequent. They typically affect immunocompromised individuals but, in some instances, can also affect an immunocompetent person. They mimic much orbital pathology clinically. Ours is a series of three patients eventually diagnosed with orbital aspergillosis but who, initially, were thought to have some other pathology.