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AbstractSevere acute respiratory syndrome coronavirus-2 (SARS-CoV-2) predisposed to the emergence of worldwide catastrophe that impels the evolution of safe and effective therapeutic system. Polyphenols as resveratrol (RSV) exhibit a well evidenced antiviral activity. Unfortunately, like most phenolic nutraceuticals, RSV suffers from restrained solubility and massive degradation in GIT and liver which in turn prohibit its clinical use. Herein, PEGylated bilosomes (PBs) contain PEGylated edge activator along with the traditional components as (Span 60, cholesterol and bile salts) were proposed to boost both permeability and bioavailability of RSV. The investigation of the prominent effect of the diverse variables on the characteristics of the vesicles and picking of the optimum formula were conducted via construction of 23 factorial experiment. The appraisal of the formulae was conducted on the basis of entrapment efficiency percent (EE%), particle size (PS) and zeta potential (ZP). In addition, the spherical shaped optimal formula (F5) exhibited EE% of 86.1 ± 2.9%, PS of 228.9 ± 8.5 nm, and ZP of −39.8 ± 1.3 mV. The sorted optimum formula (F5) exhibited superior dissolution behaviors, and boosted Caco-2 cells cellular uptake by a round 4.7 folds relative to RSV dispersion. In addition, F5 demonstrated a complete in vitro suppression of SARS-CoV-2 at a concentration 0.48 μg/ml with 6.6 times enhancement in antiviral activity relative to RSV dispersion. The accomplished molecular modeling heavily provided proof for the possible interactions of resveratrol with the key residues of the SARS-CoV2 Mpro enzyme. Finally, F5 could be proposed as a promising oral panel of RSV for curation from SARS-CoV-2 infection.

Persistent inflammation contributes to various inflammatory conditions. Inflammation-related diseases may be treated by inhibiting pro-inflammatory mediators and cytokines. Curcumin and coumarin derivatives can target signalling pathways and cellular factors to address immune-related and inflammatory ailments. This study involved designing and synthesising three series of coumarin-based analogs that incorporated curcumin and other heterocycles. These analogs were evaluated for their potential as anti-inflammatory agents in LPS-induced macrophages. Among the fourteen synthesised coumarin derivatives, compound 14b, which contained 3,4-dimethoxybenzylidene hydrazinyl, demonstrated the highest anti-inflammatory activity with an EC50 value of 5.32 μM. The anti-inflammatory effects of 14b were achieved by modulating signalling pathways like AKT/mTOR and Nrf2/HO-1, and downregulating NF-kβ, resulting in reduced production of pro-inflammatory cytokines such as IL-6, IL-1β, and TNF-α. The modelling studies revealed that 14b and dexamethasone bind to the same TNF-α pocket, suggesting that 14b has potential as a therapeutic agent superior to dexamethasone for TNF-α.

A new series of vinyl amide-, imidazolone-, and triazinone-linked combretastatin A-4 analogues have been designed and synthesised. These compounds have been evaluated for their cytotoxic activity against MDA-MB-231 breast cancer cells. The triazinone-linked combretastatin analogues (6 and 12) exhibited the most potent cytotoxic activity, in sub-micromolar concentration compared with combretastatin A-4 as a reference standard. The results of β-tubulin polymerisation inhibition assay appear to correlate well with the ability to inhibit β-tubulin polymerisation. Additionally, these compounds were subjected to biological assays relating to cell cycle aspects and apoptosis induction. In addition, the most potent compound 6 was loaded on PEG-PCL modified diamond nanoparticles (PEG-PCL-NDs) and F4 was picked as the optimum formula. F4 exhibited enhanced solubility and release over the drug suspension. In the comparative cytotoxic activity, PEG-PCL modified F4 was capable of diminishing the IC50 by around 2.89 times for nude F4, while by 3.48 times relative to non-formulated compound 6.

Morin hydrate (MH) is a widely-used Asian phytomedicinal flavonoid with a wide range of reported therapeutic activities. However, MH has limited oral bioavailability due to its low aqueous solubility and intestinal permeability, which in turn hinders its potential antiviral activity. The study reported herein was designed to encapsulate MH in polyethyleneglycolated (PEGylated) chylomicrons (PCMs) and to boost its antiviral activity and biological availability for oral administration using a rat experimental model. The PEGylated edge activator combined with the conventional components of chylomicrons (CMs) amplify the transport of the drug across the intestine and its circulation period, hence its therapeutic impact. The implementation of variables in the in vitro characterization of the vesicles was investigated. Using Design Expert® software, a 24 factorial design was conducted, and the resulting PCM formulations were fabricated utilizing a thin-film hydration technique. The efficacy of the formulations was assessed according to their zeta potential (ZP), entrapment efficiency percentage (EE%), amount of drug released after 8 h (Q8h), and particle size (PS) data. Formulation F9, which was deemed to be the optimal formula, used compritol as the lipidic core together in defined amounts with phosphatidylcholine (PC) and Brij52. Computer-aided studies revealed that MH alone in a suspension had both diminished intestinal permeability and absorption, but was enhanced when loaded in PCMs. This was affirmed by the superiority of formulation F9 results in ex vivo permeation and pharmacokinetic studies. Furthermore, formulation F9 had a superior safety profile and antiviral activity over a pure MH suspension. Molecular-docking studies revealed the capability of MH to inhibit MERS-CoV 3CLpro, the enzyme shown to exhibit a crucial role in viral replication. Additionally, F9 suppressed both MERS-CoV-induced histopathological alteration in lung tissue and resulting oxidative and inflammatory biomarkers. Collectively, the results reported herein affirmed the potential of PCMs as nanocarriers for the effective oral administration of MH as an antiviral.

VEGF plays a crucial role in cancer development, angiogenesis and progression, principally liver and breast cancer. It is vital to uncover novel chemical candidates of VEGFR inhibitors to develop more potent anti-breast and anti-liver cancer agents than the currently available candidates, sorafenib and regorafenib, that face resistance obstacles and severe side effects. Herein, nine pyrazolopyrimidine derivatives were designed, synthesized as sorafenib and regorafenib analogues and screened for their in vitro cytotoxic and growth inhibition activities against four human cancer cell lines, namely breast cancer (Michigan Cancer Foundation-7 (MCF-7), hepatocellular carcinoma (HCC) type (HepG2), lung carcinoma (A-549) and human colorectal carcinoma-116 (HCT-116)). Among the tested compounds, compounds 1, 2a, 4b and 7 showed the uppermost cytotoxic activities against all aforementioned cell lines with IC50 estimates varying from 6 to 50 µM, among which compound 7 showed the best inhibitory activity on all tested compounds. Stunningly, compound 7 showed the best significant inhibition of the VEGFR-2 protein expression level (72.3%) as compared to the control and even higher than that produced with sorafenib and regorafenib (70.4% and 55.6%, respectively). Modeling studies provided evidence for the possible interactions of the synthesized compounds with the key residues of the ATP binding sites on the hinge region and the “DFG out” motif of VEGFR-2 kinase. Collectively, our present study suggests that pyrazolopyrimidine derivatives are a novel class of anti-cancer drug candidates to inhibit VEGF-VEGFR function. Aspiring to promote constrained aqueous solubility, hence poor oral bioavailability of the developed lead molecule, 7 and 2a-charged D-α-tocopherol polyethylene glycol 1000 succinate (TPGS) surface-coated niosomes were successfully constructed, adopting a thin film hydration technique striving to overcome these pitfalls. A 23 full factorial design was involved in order to investigate the influence of formulation variables: type of surfactant, either Span 60 or Span 40; surfactant:cholesterol ratio (8:2 or 5:5) along with the amount of TPGS (25 mg or 50 mg) on the characteristics of the nanosystem. F2 and S2 were picked as the optimum formula for compounds 2a and 7 with desirability values of 0.907 and 0.903, respectively. In addition, a distinguished improvement was observed in the compound’s oral bioavailability and cytotoxic activity after being included in the nano-TPGS-coated niosomal system relative to the unformulated compound. The nano-TPGS-coated niosomal system increased the hepatocellular inhibitory activity four times fold of compound 7a (1.6 µM) and two-fold of 2a (3 µM) relative to the unformulated compounds (6 µM and 6.2 µM, respectively).

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) predisposed to the emergence of worldwide catastrophe that impels the evolution of safe and effective therapeutic system. Polyphenols as resveratrol (RSV) exhibit a well evidenced antiviral activity. Unfortunately, like most phenolic nutraceuticals, RSV suffers from restrained solubility and massive degradation in GIT and liver which in turn prohibit its clinical use. Herein, PEGylated bilosomes (PBs) contain PEGylated edge activator along with the traditional components as (Span 60, cholesterol and bile salts) were proposed to boost both permeability and bioavailability of RSV. The investigation of the prominent effect of the diverse variables on the characteristics of the vesicles and picking of the optimum formula were conducted via construction of 23 factorial experiment. The appraisal of the formulae was conducted on the basis of entrapment efficiency percent (EE%), particle size (PS) and zeta potential (ZP). In addition, the spherical shaped optimal formula (F5) exhibited EE% of 86.1 ± 2.9%, PS of 228.9 ± 8.5 nm, and ZP of −39.8 ± 1.3 mV. The sorted optimum formula (F5) exhibited superior dissolution behaviors, and boosted Caco-2 cells cellular uptake by a round 4.7 folds relative to RSV dispersion. In addition, F5 demonstrated a complete in vitro suppression of SARS-CoV-2 at a concentration 0.48 μg/ml with 6.6 times enhancement in antiviral activity relative to RSV dispersion. The accomplished molecular modeling heavily provided proof for the possible interactions of resveratrol with the key residues of the SARS-CoV2 Mpro enzyme. Finally, F5 could be proposed as a promising oral panel of RSV for curation from SARS-CoV-2 infection. [ABSTRACT FROM AUTHOR]

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A variety of situations can lead to the need for an alternative method of intraocular lens (IOL) fixation if implantation in the capsular bag is not possible. Depending on the situation, sulcus-fixated IOLs, iris-fixated IOLs (IFIOLs) and scleral-fixated IOLs (SFIOLs) are available. With SFIOLs, a distinction is made between suture-fixated and sutureless-fixated techniques. This paper summarizes the advantages and disadvantages of the different approaches, including the newer methods of sutureless SFIOLs. The decision on a specific approach in the individual case depends on both the individual circumstances of the patient and the experience of the surgeon., (© 2024. The Author(s).)

A gastrointestinal bleed (GIB) in the setting of metastatic insulinoma is a rare phenomenon. It appears that cases of metastatic insulinoma causing GIB are rare, often influenced by the tumor's location. Our case involves an 82-year-old male with dementia and a history of recurrent hypoglycemia, presenting with an episode of altered mental status. The patient exhibited hypoglycemia alongside a melena episode and anemia. Diagnostic criteria, including Whipple's triad, confirmed endogenous insulin production. Computed tomography (CT) showed a left paraaortic/retroperitoneal mass. Esophagogastroduodenoscopy (EGD) visualized an extrinsic mass at the gastric body, which caused an ulcerated surface that was treated with clipping and hemostasis. The patient's recurrent hypoglycemic episodes were treated with glucose, while his GIB was managed with hemostasis and clipping. However, the patient was not a surgical candidate, and further medical treatment was ceased by the family., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Boateng et al.)

Background: Common bile duct dilatation alone or double duct sign (both CBD and dilated pancreatic duct dilatation) and abnormal liver enzymes are highly predictive of biliary disease. This can be identified on ultrasound (US), CT scan, and/or magnetic resonance cholangiopancreatography (MRCP). Unexplained dilatation on imaging might warrant endoscopic ultrasound (EUS) to identify any occult causes. Supporting literature about the importance of using EUS in these conditions is evolving with no clear evidence-based approach to evaluate asymptomatic dilated ducts.We aim to investigate the diagnostic yield of EUS in unexplained CBD dilatation or double duct sign with normal liver enzymes., Method: A retrospective data analysis was conducted from January 2015 to October 2021 on asymptomatic patients with a dilatated CBD of 7 mm or more and 9 mm if the patient had a cholecystectomy history or double duct sign with normal liver enzymes., Result: 32 EUS procedures were indicated for unexplained dilated CBD or double duct sign on imaging with normal liver enzymes. 23 had CBD dilatation alone (72 %), and 9 had a double duct sign (28 %). 20 of the included patients were females (63 %), and 12 were males (37 %), with a mean age of 63.8 ± 17 and 68.2 ± 14 years old, respectively (p = 0.424). The diagnosis after EUS in CBD dilatation alone showed a yield of 56 % as follow; no pathology in 10 (44 %), sludge in 9 patients (39 %), CBD stone in 3 (13 %), malignant stricture in 1 (4 %) (Fig. 1). On the other hand, EUS in those with double duct signs showed a diagnostic yield of 55 %; no pathology in 4 (45 %), pancreatic head adenocarcinoma in 3 patients (33 %), Biliary stone in one patient, and malignant CBD stricture in one patient (11 % each) (Fig. 2)., Conclusion: Unexplained CBD dilatation or Double duct sign on imagining in patients with normal liver enzymes should warrant further investigation with EUS to avoid missing serious pathological conditions such as stones, sludge, stricture, or a mass., Competing Interests: Conflicts of interest: None of the authors have any conflicts of interest to declare., (© 2024 Greater Baltimore Medical Center.)

Glomus tumor is a rare mesenchymal tumor commonly located in the periphery of glomus bodies, such as the subungual regions (e.g., fingernails and toenails). Other locations include the forearm, wrist, or trunk. Even rare is when these tumors are found in the submucosa. In the stomach, it is commonly found at the gastric antrum. Gastric glomus tumors (GGTs) are often found incidentally after a presumption of other gastric tumors is diagnosed, such as gastrointestinal stromal tumors (GISTs) or carcinoid tumors. The variable clinical presentation of GGT and the fact that histology is the only way to confirm the diagnosis is what makes GGT such an elusive tumor. Our case is a patient that presented with weight loss and reflux. Esophagogastroduodenoscopy (EGD) and colonoscopy were done, and the diagnosis of carcinoid tumor was presumed. Preliminary pathology was suggestive of a diagnosis of carcinoid tumor. The patient eventually had a subtotal gastrectomy, and a biopsy with immunohistochemical staining of the specimen was received, finally confirming the diagnosis of a GGT., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, Ezeh et al.)

Glomus tumors are rare neoplasms originating from smooth muscle cells of the glomus body. They rarely involve the gastrointestinal tract, and when they do, they present as acute gastrointestinal bleeds with symptoms such as hematemesis or melena. We present a rare case of a gastric glomus tumor in a 50- year- old male presenting with shortness of breath and gastrointestinal bleed requiring transfusions. Coincidently, he was also found to have a pulmonary embolism that usually would require anticoagulation, which was contraindicated in an active gastrointestinal bleed. He eventually required an inferior vena cava (IVC) filter and underwent a partial gastrectomy. Due to gastric glomus tumor being a rare entity, there is a paucity of data to have a classification and grading or staging system, and tumors are usually considered benign. The exact diagnosis is dependent on histopathological findings as it can mimic a gastrointestinal stromal tumor (GIST). Pulmonary embolism, a common phenomenon, can often be seen in patients with malignancy. Our patient was diagnosed with a glomus tumor which is usually benign. As per our literature search, there are no documented cases of GGT with concomitant Pulmonary embolism diagnosis that would point to a causal association., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2022, Ezeh et al.)

Direct-acting antiviral (DAA) therapy is often well-tolerated, and adverse events from DAA therapy are uncommon. We report a case of a woman who underwent orthotopic liver transplant for chronic hepatitis C infection and later developed alloimmune hepatitis shortly after starting DAA therapy for recurrent hepatitis C infection. The patient developed acute alloimmune hepatitis approximately 2 weeks after starting treatment with sofosbuvir, velpatasvir, and voxilaprevir. This case report proposes a dysregulation of immune surveillance due to the DAA stimulation of host immunity and rapid elimination of hepatitis C viral load as a precipitating factor for the alloimmune process, leading to alloimmune hepatitis in a post-transplant patient who starts on DAA., Competing Interests: Dr. Pyrsopoulos is a recipient of research grants from Bayer, Beigene, Intercept, Mallinckrodt, Eisai, Novartis, Resusix, Saro, Valeant, Gilead, Genfit, Grifols, Prometheus, and Zydus. Dr. Pyrsopoulos has also served as a consultant for Bayer and Eisai. Dr. Guarrera is a recipient of research grants from and has served a consultant for Organ Recovery Systems Inc for work in Organ Preservation. The other authors have no conflict of interests related to this publication., (© 2020 Authors.)

Acute esophageal necrosis (AEN) is a rare and often fatal pathology of unclear etiology affecting the distal two-thirds of the esophagus. Typically, elderly patients with multiple comorbidities present with signs of upper gastrointestinal (GI) hemorrhage. On endoscopy, the mucosa is black due to ischemic necrosis, resulting in the commonly used term "black esophagus." We present a rare case of a 61-year-old male presenting with shortness of breath and hematemesis diagnosed as AEN through endoscopy. This case illustrates the importance of considering AEN as part of differential diagnoses in a rising elderly population with multiple comorbidities that present with upper GI hemorrhage. Treatment should be aimed at maintaining hemodynamic stability with high-dose proton pump inhibitors., (Copyright: © International Journal of Health Sciences.)

Gastrointestinal stromal tumors are uncommon when compared to all gastrointestinal neoplasms but are the most common mesenchymal tumors of the gastrointestinal tract. The largest gastrointestinal stromal tumor ever recorded in literature weighed approximately 6.1 kg and measured 39 cm × 27 cm × 14 cm. About two-thirds of GISTs are malignant. The tumor size, mitotic rate, cellularity, and nuclear pleomorphism are the most important parameters when considering prognosis and recurrence. The definitive treatment for these tumors is resection. In the year 2000, the first patient was treated with the tyrosine kinase inhibitor imatinib and since then, gastrointestinal stromal tumors with high-risk features have been treated successfully with tyrosine kinase inhibitors. We present the largest gastrointestinal stromal tumor recorded in medical literature measuring 42.0 cm × 31.0 cm × 23.0 cm in maximum dimensions and weighing in at approximately 18.5 kg in a 65-year-old African-American male who presented with increased abdominal distention. The mass was successfully excised, and the patient was treated with imatinib without local or distant recurrence 1.5 years postoperatively.

Previous studies have shown a higher prevalence of malignancy in patients with diabetes mellitus (DM) and chronic kidney disease (CKD). The purpose of this study was to investigate the prevalence of adenomatous colon polyps (ACP) as they occur in subjects with DM and coexisting CKD. This is a retrospective cohort study of patients with DM (n=565) who had undergone colonoscopy between 2000-2010. The cohort was further bifurcated into those with CKD (n=296) and those with normal renal function (n=269). Presence or absence of ACP was measured in both groups. Concentrations of serum parathyroid hormone (PTH), Calcium (Ca), and phosphorous (P) were recorded for the CKD group. The levels of these variables in patients with ACP (n=171) were compared with the levels from those without ACP (n=175). Nonparametric statistical methods were applied with statistical significance suggested by p<0.05 (two-sided). The presence of CKD in this cohort demonstrated a significant association with ACP (OR: 2.96; 95% CI: 2.02 to 4.34; p<0.0001). We did not detect a statistically significant difference in P or Ca between the groups. There was, however, a statistically significant difference in PTH; for the group with ACP, PTH: 387.7±351.3 ng/L vs. 172.2±196.7 ng/L; p<0.0001. This data suggests that CKD is associated with ACP in subjects with DM and those with ACP exhibit higher PTH levels when compared to those without ACP., (© 2016 by the Association of Clinical Scientists, Inc.)

Hepatocellular carcinoma (HCC) usually occurs in patients with underlying risk factors such as liver cirrhosis and chronic hepatitis B. Although patients with Crohn's disease (CD) are at an increased risk to develop malignancies such as colon cancer, the incidence of HCC in this population is extremely rare. We report a case of 62-year-old male with long history of CD treated with azathioprine (AZA) and aminosalicylic acid (ASA) who was incidentally diagnosed with HCC, for which left hepatectomy was done. Four years later during routine follow-up, patient had another hepatic lesion and underwent resection of the mass. The mechanism of occurrence of HCC in patient with CD is still controversial and may include immune mediated changes and medication related complications. AZA was reported in all case reports of CD that developed HCC. Through this report we hope to explore the complex pathophysiological mechanisms contributing to the development of HCC in the Crohn's disease patient population.

Background: Age-related macular degeneration (ARMD) is the leading cause of blindness in people over 65 years of age. A rapid loss of vision occurs especially in cases with choroidal neovascularisation. Early detection of ARMD and timely treatment are mandatory. We have prospectively studied the results of two diagnostic self tests for the early detection of metamorphopsia and scotoma, the PHP test and the Amsler grid test, in different stages of ARMD., Patients and Methods: Patients with ARMD and best corrected visual acuity of 6/30 or better (Snellen charts) were examined with a standardised protocol, including supervised Amsler grid examination and PHP, a new device for metamorphopsia or scotoma measurement, based on the hyperacuity phenomenon in the central 14 degrees of the visual field. The stages of ARMD were independently graded in a masked fashion by stereoscopic ophthalmoscopy, stereoscopic fundus colour photographs, fluorescein angiography, and OCT. The patients were subdivided into 3 non-neovascular groups [early, late (RPE atrophy > 175 microm) and geographic atrophy], a neovascular group (classic and occult CNV) and an age-matched control group (healthy volunteers)., Results: 140 patients, with ages ranging from 50 to 90 years (median 68 years), were included in the study. Best corrected visual acuity ranged from 6/30 to 6/6 with a median of 6/12. 95 patients were diagnosed as non-neovascular ARMD. Thirty eyes had early ARMD (9 were tested positive by the PHP test and 9 by the Amsler grid test), and 50 late ARMD (positive: PHP test 23, Amsler grid test 26). The group with geographic atrophy consisted of 15 eyes (positive: PHP test 13, Amsler grid test 10). Forty-five patients presented with neovascular ARMD (positive: PHP test 38, Amsler grid test 36), 34 volunteers served as control group (positive: PHP test 1, Amsler grid test 5)., Conclusions: The PHP and Amsler grid tests revealed comparable results detecting metamorphopsia and scotoma in early ARMD (30 vs. 30 %) and late ARMD (46 vs. 52 %). However, the PHP test more often revealed disease-related functional changes in the groups of geographic atrophy (87 vs. 67 %) and neovascular ARMD (84 vs. 80 %). This implies that the PHP and Amsler grid self tests are useful tools for detection of ARMD and that the PHP test has a greater sensitivity in the groups of geographic atrophy and neovascular AMD.

A new methodology for focusing ultrasonic beams noninvasively in the presence of the rib cage is investigated. This investigation is motivated by the need to employ high intensity focused ultrasound (HIFU) using phased array applicators for the treatment of liver tumors partially shadowed by the rib obstacles. This approach enables us to efficiently perform the ultrasound computational analysis and pattern synthesis in the interior region of the rib cage. The proposed technique consists of two main steps. First, a virtual array is introduced along the intercostal spacings between the solid ribs to generate the prespecified intensity levels at a set of control points within the target region. The second step involves the design of the actual feed array that induces the virtual sources between the intercostal spacings. This design optimization is carried out via the pseudo-inverse technique (minimum norm least squares solution) and by enforcing a constrained preconditioned pseudo-inverse method. The proposed procedure calculates the required primary sources (feed array) while maintaining minimal power deposition over the solid obstacles.

A computationally efficient hybrid ray-physical optics (HRPO) model is presented for the analysis and synthesis of multiple-focus ultrasound heating patterns through the human rib cage. In particular, a ray method is used to propagate the ultrasound fields from the source to the frontal plane of the rib cage. The physical-optics integration method is then employed to obtain the intensity pattern inside the rib cage. The solution of the matrix system is carried out by using the pseudo inverse technique to synthesize the desired heating pattern. The proposed technique guides the fields through the intercostal spacings between the solid ribs and, thus, minimal intensity levels are observed over the solid ribs. This simulation model allows for the design and optimization of large-aperture phased-array applicator systems for noninvasive ablative thermal surgery in the heart and liver through the rib cage.