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Objective. Melorheostosis is a rare, non-hereditary, benign bone disease characterized by abnormal bone growth. Generally, melorheostosis develops during childhood or adolescence and progresses gradually over time. This disease represents a true challenge to the physician because of its variability due to location, extension of the affected bone, and involvement of associated soft tissue. Pain management, physical therapy, and surgery may be recommended, depending on the individual case. This review aims to get an overview of the latest evidence relating to epidemiology, clinical and radiographic characteristics, diagnosis, and possible therapeutic strategies for melorheostosis and describe our experience through a clinical case. Methods. We designed a comprehensive literature search on melorheostosis in MEDLINE (via Pubmed) up to April 2023 and reviewed reports published in international journals. Results. The purpose is to highlight the importance of a multidisciplinary approach in the management of a rare disease such as melorheostosis. We discuss the role of different physicians, including genetists, rheumatologists, physiatrists, physical therapists, and orthopedic surgeons, in providing accurate diagnoses and effective treatments. We conducted a comprehensive review of the literature on the treatment of melorheostosis to support these findings. In addition, the article presents a case study of a patient suffering from melorheostosis, focusing on difficulties in reaching a correct diagnosis and attempts towards conservative and surgical interventions. The patient underwent hip arthroplasty, and the final result was an improvement in function and a reduction in pain. Conclusions. Managing melorheostosis can be challenging, and there is no standardized treatment for this condition at the moment.

This study investigated the effects of the new aldose reductase inhibitor benzofuroxane derivative 5(6)-(benzo[d]thiazol-2-ylmethoxy)benzofuroxane (BF-5m) on the prolongation of cardiac QT interval and increase of coronary perfusion pressure (CPP) in isolated, high glucose (33.3 mM D-glucose) perfused rat hearts. BF-5m was dissolved in the Krebs solution at a final concentration of 0.01 μM, 0.05 μM, and 0.1 μM. 33.3 mM D-glucose caused a prolongation of the QT interval and increase of CPP up to values of 190 ± 12 ms and 110 ± 8 mmHg with respect to the values of hearts perfused with standard Krebs solution (11.1 mM D-glucose). The QT prolongation was reduced by 10%, 32%, and 41%, respectively, for the concentration of BF-5m 0.01 μM, 0.05 μM, and 0.1 μM. Similarly, the CPP was reduced by 20% for BF-5m 0.05 μM and by 32% for BF-5m 0.1 μM. BF-5m also increased the expression levels of sirtuin 1, MnSOD, eNOS, and FOXO-1, into the heart. The beneficial actions of BF-5m were partly abolished by the pretreatment of the rats with the inhibitor of the sirtuin 1 activity EX527 (10 mg/kg/day/7 days i.p.) prior to perfusion of the hearts with high glucose + BF-5m (0.1 μM). Therefore, BF-5m supplies cardioprotection from the high glucose induced QT prolongation and increase of CPP.

The study investigated the effects of the aldose reductase (AR) inhibitor benzofuroxane derivative 5(6)-(benzo[d]thiazol-2-ylmethoxy) benzofuroxane (herein referred to as BF-5m) on the biochemical and tissue alterations induced by endotoxic uveitis in rats. BF-5m has been administered directly into the vitreous, in order to assess the expression and levels of (i) inflammatory markers such as the ocular ubiquitin-proteasome system, NF-κB, TNF-α, and MCP-1; (ii) prooxidant and antioxidant markers such as nitrotyrosine, manganese superoxide dismutase (MnSOD), and glutathione peroxidase (GPX); (iii) apoptotic/antiapoptotic factors caspases and Bcl-xl; (iv) markers of endothelial progenitor cells (EPCs) recruitment such as CD34 and CD117. 5 μL of BF-5m (0.01; 0.05; and 0.1 μM) into the right eye decreased in a dose-dependent manner the LPS-induced inflammation of the eye, reporting a clinical score 1. It reduced the ocular levels of ubiquitin, 20S and 26S proteasome subunits, NF-κB subunits, TNF-α, MCP-1, and nitrotyrosine. BF-5m ameliorated LPS-induced decrease in levels of MnSOD and GPX. Antiapoptotic effects were seen from BF-5m by monitoring the expression of Bcl-xl, an antiapoptotic protein. Similarly, BF-5m increased recruitment of the EPCs within the eye, as evidenced by CD34 and CD117 antibodies.

Sarcomas are rare malignancies with over 100 distinct histological subtypes. Their rarity and heterogeneity pose significant challenges to identifying effective therapies, and approved regimens show varied responses. Novel, personalized approaches to therapy are needed to improve patient outcomes. Patient-derived tumor organoids (PDTOs) model tumor behavior across an array of malignancies. We leverage PDTOs to characterize the landscape of drug resistance and sensitivity in sarcoma, collecting 194 specimens from 126 patients spanning 24 distinct sarcoma subtypes. Our high-throughput organoid screening pipeline tested single agents and combinations, with results available within a week from surgery. Drug sensitivity correlated with clinical features such as tumor subtype, treatment history, and disease trajectory. PDTO screening can facilitate optimal drug selection and mirror patient outcomes in sarcoma. We could identify at least one FDA-approved or NCCN-recommended effective regimen for 59% of the specimens, demonstrating the potential of our pipeline to provide actionable treatment information., Competing Interests: Declaration of interests A.S., J.Y., P.C.B., and N.C.F. are founders and owners of Icona BioDx. A.S. is a founder and owner of MiRiO., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Itraconazole (ITZ) is one of the broad-spectrum antifungal agents for treating fungal keratitis. In clinical use, ITZ has problems related to its poor solubility in water, which results in low bioavailability when administered orally. To resolve the issue, we formulated ITZ into the inclusion complex (ITZ-IC) system using β-cyclodextrin (β-CD), which can potentially increase the solubility and bioavailability of ITZ. The molecular docking study has confirmed that the binding energy of ITZ with the β-CD was -5.0 kcal/mol, indicating a stable conformation of the prepared inclusion complex. Moreover, this system demonstrated that the inclusion complex could significantly increase the solubility of ITZ up to 4-fold compared to the pure drug. Furthermore, an ocular drug delivery system was developed through dissolving microneedle (DMN) using polyvinyl pyrrolidone (PVP) and polyvinyl alcohol (PVA) as polymeric substances. The evaluation results of DMN inclusion complexes (ITZ-IC-DMN) showed excellent mechanical strength and insertion ability. In addition, ITZ-IC-DMN can dissolve rapidly upon application. The ex vivo permeation study revealed that 75.71% (equivalent to 3.79 ± 0.21 mg) of ITZ was permeated through the porcine cornea after 24 h. Essentially, ITZ-IC-DMN exhibited no signs of irritation in the HET-CAM study, indicating its safety for application. In conclusion, this study has successfully developed an inclusion complex formulation containing ITZ using β-CD in the DMN system. This approach holds promise for enhancing the solubility and bioavailability of ITZ through ocular administration.

Existing conventional antithrombosis drugs have caused many side effects, opening up opportunities for the development of new thrombotic drugs. There is potential to use the hispidulin-rich fraction of sesewanua (HRFS) as a new antithrombotic. The oral route limitation of hispidulin, as a low water solubility and non-polar compound, can be addressed. This study explores the potential of HRFS in the form of dissolving microneedles (DMN). The formula was created using polymers such as polyvinyl alcohol (PVA), polyvinyl pyrrolidone K-30 (PVP), and non-ionic surfactant. Ex vivo permeation studies found that 184.95 µg/cm 2 of hispidulin was released 60 h after the best formulation. After 14 days of applying HRFS-DMN, the anticoagulant and antioxidant activity in male albino rats showed higher Activated Partial Thromboplastin Time (aPTT) and Prothrombin Time (PT) values and lower Inter Cellular Adhesion Molecule-1 (ICAM-1) values. No statistically significant differences were found between the effects of two and four HRFS-DMN and the injection of heparin at a dosage of 200 IU per kilogram. However, notable distinctions were observed when comparing HRFS-DMN to negative controls, oral and quercetin as positive controls at anti-ICAM activity. The findings confirmed the feasibility of HRFS-DMN for thrombosis and its effectiveness in delivering Hispidulin (HIS) into the bloodstream. This DMN is non-irritating, safe, and painless, showing promising outcomes in enhancing the efficacy of thrombosis treatment via the transdermal route., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

High Grade Serous Ovarian Cancer (HG-SOC), the most prevalent and aggressive gynecological malignancy, is marked by ubiquitous loss of functional p53, largely due to point mutations that arise very early in carcinogenesis. These mutations often lead to p53 protein misfolding and subsequent aggregation, yet the alterations in intracellular p53 dynamics throughout ovarian cancer progression remain poorly understood. HG-SOC originates from the fallopian tube epithelium, with a well-documented stepwise progression beginning with early pre-malignant p53 signatures. These signatures represent largely normal cells that express and accumulate mutant p53, which then transform into benign serous tubal intraepithelial lesions (STIL), progress into late pre-malignant serous tubal intraepithelial carcinoma (STIC), and ultimately lead to HGSOC. Here, we show that the transition from folded, soluble to aggregated mutant p53 occurs during the malignant transformation of benign precursor lesions into HGSOC. We analyzed fallopian tube tissue collected from ten salpingo-oophorectomy cases and determined the proportion of cells carrying soluble versus mis-folded/mutant p53 through conformation-sensitive staining and quantification. Misfolded p53 protein, prone to aggregation, is present in STICs and HG-SOCs, but notably absent from preneoplastic lesions and surrounding healthy tissue. Overall, our results indicate that aggregation of mutant p53 is a structural defect that distinguishes preneoplastic early lesions from late premalignant and malignant ones, offering a potential treatment window for targeting p53 aggregation and halting ovarian cancer progression.

Phenylketonuria (PKU, OMIM 261600) is a genetic disorder caused by a deficiency of the hepatic enzyme phenylalanine hydroxylase (PAH). If left untreated, PKU leads to systemic phenylalanine (Phe) accumulation, which can result in irreversible brain damage and intellectual disabilities. In the last 60 years, early and strict dietary restriction of phenylalanine (Phe) intake proved to prevent the severe clinical phenotype of untreated PKU. While the specific mechanisms through which phenylalanine causes brain damage are still poorly understood, preclinical models have been deeply explored to characterize the neurotoxic effect of Phe on neurodevelopmental processes. At the same time, that on the aging brain still needs to be explored. In the brain of untreated PAH Enu2(-/-) mouse, we previously reported a reduction of myelin basic protein (MBP) during postnatal development up to 60 PND. Later in the diseased mouse's life, a spontaneous and persistent restoration of MBP was detected. In this present longitudinal study, ranging from 14 to 540 post-natal days (PND) of untreated PAH Enu2(-/-) mice, we further investigated: a) the long-life consistency of two Phe-related brain metabolic alterations, such as large neutral amino acids (LNAA) and biogenic amine neurotransmitters' depletion; b) the outcome of locomotor functions during the same life span; c) the integrity of myelin as assessed ex vivo by central (hippocampus) and peripheral (extensor digitorum longus-sciatic nerve) action potential conduction velocities. In contrast with the results of other studies, brain Leu, Ile, and Val concentrations were not significantly altered in the brain PAH Enu2(-/-) mouse. On the other hand, 3-O-Methyldopa (3-OMD, a biomarker of L-DOPA), serotonin, and its associated metabolites were reduced throughout most of the considered time points, with consistent reductions observed prevalently from 14 to 60 PND. Normal saltatory conduction was restored after 60 PND and remained normal at the last examination at 360 PND, resulting nonetheless in a persistent locomotor impairment throughout a lifetime. These new findings contribute to laying the foundations for the preclinical characterization of aging in PKU, confirming neurotransmitter defects as consistent metabolic traits. LNAAs have a minor role, if any, in brain damage pathogenesis. Transient myelin synthesis failure may impact brain connectivity during postnatal development but not nervous signal conduction., Competing Interests: Declaration of competing interest Mauro Magnani and Luigia Rossi hold shares in EryDel SpA, a company with interests in the technology of RBC-based drug delivery. The other authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Drug repurposing is a promising approach to identify new pharmacological indications for drugs that have already been established. However, there is still a limitation in the availability of a high-throughput in vivo preclinical system that is suitable for screening and investigating new pharmacological indications. The aim of this study was to introduce the application of Drosophila larvae as an in vivo platform to screen drug candidates with anti-aging and immunomodulatory activities. To determine whether Drosophila larvae can be utilized for assessing anti-aging and immunomodulatory activities, phenotypical and molecular assays were conducted using wildtype and mutant lines of Drosophila . The utilization of mutant lines ( PGRP-LBΔ and Psh[1];;ModSP[KO] ) mimics the autoinflammatory and immunodeficient conditions in humans, thereby enabling a thorough investigation of the effects of various compounds. The phenotypical assay was carried out using survival and locomotor observation in Drosophila larvae and adult flies. Meanwhile, the molecular assay was conducted using the RT-qPCR method. In vivo survival analysis revealed that caffeine was relatively safe for Drosophila larvae and exhibited the ability to extend Drosophila lifespan compared to the untreated controls, suggesting its anti-aging properties. Further analysis using the RT-qPCR method demonstrated that caffeine treatment induced transcriptional changes in the Drosophila larvae, particularly in the downstream of NF-κB and JAK-STAT pathways, two distinct immune-related pathways homologue to humans. In addition, caffeine enhanced the survival of Drosophila autoinflammatory model, further implying its immunosuppressive activity. Nevertheless, this compound had minimal to no effect on the survival of Staphylococcus aureus- infected wildtype and immunodeficient Drosophila , refuting its antibacterial and immunostimulant activities. Overall, our results suggest that the anti-aging and immunosuppressive activities of caffeine observed in Drosophila larvae align with those reported in mammalian model systems, emphasizing the suitability of Drosophila larvae as a model organism in drug repurposing endeavors, particularly for the screening of newly discovered chemical entities to assess their immunomodulatory activities before proceedings to investigations in mammalian animal models., Competing Interests: All the authors declare that there are no conflicts of interest., (© 2024 The Author(s).)

Introduction: Elbow fractures, characterized by their complexity, present significant challenges in post-surgical recovery, with rehabilitation playing a critical role in functional outcomes. This study explores the efficacy of rehabilitative interventions in enhancing joint range of motion (ROM) and reducing complications following surgery for both stable and unstable elbow fractures., Methods: A cohort of 15 patients, divided based on the stability of their elbow fractures and whether they received post-operative rehabilitation, was analyzed retrospectively. Measurements of ROM-including flexion, extension, pronation, and supination-were taken at three follow-ups: 15-, 30-, and 45-day post surgery. The study assessed the impact of rehabilitation on ROM recovery and the resolution of post-surgical complications., Results: The findings indicated no statistically significant differences in ROM improvements between patients who underwent rehabilitation and those who did not, across all types of movements measured. However, early rehabilitative care was observed to potentially aid in the mitigation of complications such as joint stiffness, especially in patients with stable fractures., Conclusion: While rehabilitation did not universally improve ROM recovery in elbow fracture patients, it showed potential in addressing post-operative complications. The study underscores the importance of individualized rehabilitation plans and highlights the need for further research to establish evidence-based guidelines for post-surgical care in elbow fractures., (© 2024. The Author(s).)

Background: Reports on hand dysfunction and rehabilitation in SSc are quite scarce in the literature and mainly focus on functional assessment tools, such as the Duruoz Hand Index and the HAMIS test for evaluating hand mobility by simulating specific grasps with nine different objects., Purpose of the Study: This study aimed to provide an adequate assessment methodology for hand grasp dysfunctions in patients suffering from systemic sclerosis (SSc) through the 16-grasp test., Study Design: Case-control study., Methods: Ninety-seven consecutive SSc patients were recruited at our Scleroderma Unit, where a 16-grasp test was performed by all patients and supervised by an experienced hand therapist. Sixteen different patterns of grasp have been divided into power grasps and precision pinch and two more modalities: static and dynamic prehension evaluation on scale from 0 to 4. We also compared previous evaluations on 19 of patients recruited., Results: The majority of SSc patients (84 females and 13 males; mean age 56.0±12.0 years; mean disease duration 8.0±6.0 years) displayed grasp dysfunctions; in particular 48% and 54% reported slight difficulty in the right and left grasps respectively, 6% medium difficulty in both hands, and only 3% and 1% experienced severe difficulty respectively, while 31.5% had no issues in either hand. Our results showed that the limited cutaneous subset (lcSSc) scored a lower deficit for either grasp compared to diffuse form (dcSSc). No statistically significant differences in total grasp deficit had been noticed when comparing patients having a disease duration < 5 years or longer. In the retrospective study on 19 of these patients, 8 out of 10 lcSSc patients showed no significant changes, while in 2 out of 10, slight improvements were observed in both hands. However, in the dcSSc group, 4 out of 9 worsened bilaterally while the grasp scores for 5 of them remained unchanged., Conclusion: Our study reported hand involvement in both lcSSc and dcSSc forms, more significantly in dcSSc patients. This test is intended to be a more objective means of assessing grasp alterations linked to scleroderma hand deformities. Furthermore, thanks to its intuitiveness, the test may be useful for engineers designing personalized ergonomic assistive devices., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

COVID-19 has been a challenging outbreak to face, with millions of deaths among the globe. Acute respiratory failure due to interstitial pneumonia was the leading cause of death other than prothrombotic activation and complications. Lung ultrasound (LUS) and point-of-care ultrasound (POCUS) are widely used not only to triage, to identify, and to monitor lungs involvement but also to assess hemodynamic status and thrombotic and hemorrhagic complications, mainly in critically ill patients. POCUS has gained growing consideration due to its bedside utilization, reliability, and reproducibility even in emergency settings especially in unstable patients. In this narrative review, we aim to describe LUS and POCUS utilization in COVID-19 infection based on the literature found on this topic. We reported the LUS patterns of COVID-19 pulmonary infection, the diagnostic accuracy with respect to CT lung scan, its prognostic value, the variety of scores and protocols proposed, and the utilization of POCUS to investigate the extra-lung complications.

Sildenafil citrate (SIL) as a first-line treatment for erectile dysfunction is currently reported to have poor solubility and bioavailability. Moreover, SIL undergoes first-pass metabolism when taken orally and its injection can lead to discomfort. In this study, we introduce a novel transdermal delivery system that integrates hydrogel-forming microneedles with the inclusion complex tablet reservoir. The hydrogel-forming microneedle was prepared from a mixture of polymers and crosslinkers through a crosslinking process. Importantly, the formulations showed high swelling capacity (>400 %) and exhibited adequate mechanical and penetration properties (needle height reduction < 10 %), penetrating up to five layers of Parafilm® M (assessed to reach the dermis layer). Furthermore, to improve the solubility of SIL in the reservoir, the SIL was pre-complexed with β-cyclodextrin. Molecular docking analysis showed that SIL was successfully encapsulated into the β-cyclodextrin cavity and was the most suitable conformation compared to other CD derivatives. Moreover, to maximize SIL delivery, sodium starch glycolate was also added to the reservoir formulation. As a proof of concept, in vivo studies demonstrated the effectiveness of this concept, resulting in a significant increase in AUC (area under the curve) compared to that obtained after administration of pure SIL oral suspension, inclusion complex, and Viagra® with relative bioavailability > 100 %. Therefore, the approach developed in this study could potentially increase the efficacy of SIL in treating erectile dysfunction by being non-invasive, safe, avoiding first-pass metabolism, and increasing drug bioavailability., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Objective: Melorheostosis is a rare, non-hereditary, benign bone disease characterized by abnormal bone growth. Generally, melorheostosis develops during childhood or adolescence and progresses gradually over time. This disease represents a true challenge to the physician because of its variability due to location, extension of the affected bone, and involvement of associated soft tissue. Pain management, physical therapy, and surgery may be recommended, depending on the individual case. This review aims to get an overview of the latest evidence relating to epidemiology, clinical and radiographic characteristics, diagnosis, and possible therapeutic strategies for melorheostosis and describe our experience through a clinical case., Methods: We designed a comprehensive literature search on melorheostosis in MEDLINE (via Pubmed) up to April 2023 and reviewed reports published in international journals., Results: The purpose is to highlight the importance of a multidisciplinary approach in the management of a rare disease such as melorheostosis. We discuss the role of different physicians, including genetists, rheumatologists, physiatrists, physical therapists, and orthopedic surgeons, in providing accurate diagnoses and effective treatments. We conducted a comprehensive review of the literature on the treatment of melorheostosis to support these findings. In addition, the article presents a case study of a patient suffering from melorheostosis, focusing on difficulties in reaching a correct diagnosis and attempts towards conservative and surgical interventions. The patient underwent hip arthroplasty, and the final result was an improvement in function and a reduction in pain., Conclusions: Managing melorheostosis can be challenging, and there is no standardized treatment for this condition at the moment.

Background: Delivery by cesarean section (SC) increases the risk of a surgical site infection (SSI). Therapy from health services and complementary therapy reduce the risk of infection and accelerate the wound-healing process. This study compared wound healing after SC with a turmeric extract gel and original Trigona honey., Methods: Female white rats ( Rattus novergicus ) with pre- and post-testing and a control group were included in this experiment, which was conducted in June-July 2022. The test animals were 56 female white rats, 2-4 months old, weighing 150-350 g. The treatment group was divided into three subgroups with application of 50% and 75% turmeric extract gel and Trigona honey. The turmeric was given twice daily, and the honey was divided into two applications of twice a day and once a day. Wounds were assessed using the Reeda Scale., Results: The fastest wound healing occurred in the group given Trigona honey twice daily. Redness, ecchymosis, and edema disappeared in this group on day 9 (score 0), and granulation tissue formed on day 9. The group that was administered 50% and 75% turmeric gel extract and Trigona honey once a day healed by days 12 and 15, respectively; all three of these interventions were better than the control group., Conclusions: Administering Trigona honey twice daily was more effective for accelerating wound healing than the 50% or 75% turmeric extract gel. Original Trigona honey has the potential to be a post-SC wound healing agent., Competing Interests: No competing interests were disclosed., (Copyright: © 2024 Nilawati Usman A et al.)

Acute respiratory failure (ARF) is a challenging condition that clinicians, especially in emergency settings, have to face frequently. Especially in emergency settings, many underlying diseases can lead to ARF and life-threatening conditions have to be promptly assessed and correctly treated to avoid unfavorable outcomes. In recent years, point-of-care ultrasound (POCUS) gained growing consideration due to its bedside utilization, reliability and reproducibility even in emergency settings especially in unstable patients. Research on POCUS application to assess ARF has been largely reported mainly with observational studies showing heterogeneous results from many different applications. This narrative review describes the wide potentiality of POCUS to face airways and breathing life-threatening conditions such as upper airway management, pulmonary and pleural pathologies and diaphragm impairment. We conducted extensive research of the literature to report from major studies to case reports deemed useful in practical clinical utilization of POCUS in ARF. Due to the huge amount of the literature found, we focused on airways and breathing assessment trying to systematize the evidence according to clinical care of ARF in emergency settings. Further studies, possibly trials, should determine how POCUS is crucial in clinical practice in terms of standard of care improvements, patient safety and cost-benefit analysis.