Significant Systemic Effects Research Articles

Clinical Manifestations and Implications of Nonneoplastic Uveitis Masquerade Syndrome

To investigate the clinical manifestations and systemic and ocular implications of nonneoplastic uveitis masquerade syndrome (NNUMS). Retrospective case series. The clinical data of 830 consecutive patients who presented with uveitis at a tertiary referral center in northern Taiwan between August 2013 and August 2020 were analyzed. The clinical characteristics and outcomes of patients with NNUMS were evaluated. Overall, 3.7% of patients were determined to have uveitis masquerade syndrome. Among them, 24 patients (77%; 34 eyes) were diagnosed as having NNUMS. The main presenting anatomical location was posterior uveitis (58.8%). In the NNUMS group, a high chorioretinal involvement rate (94.1%) and delayed diagnosis from symptom onset (45.8% cases were diagnosed after more than 90 days) were found. Multimodal imaging was the major decisive diagnostic factor. Systemic condition alterations requiring urgent treatment were noted in 29.2% of cases. Ocular complications were noted in 58.8% of cases; 60% of those were observed on referral. Following appropriate treatment, visual acuity could be maintained in 88.3% of cases. The 5 major categories of NNUMS were retinal vascular disorders, rhegmatogenous retinal detachment, retinal dystrophy, central serous chorioretinopathy, and uveal effusion syndrome. NNUMS is a group of heterogeneous diseases with a complex diagnostic process and significant ocular and systemic effects. High awareness regarding common clinical manifestations is crucial for physicians to make the appropriate diagnosis and management.

Use of Systemic Mycophenolate Mofetil Therapy in Ocular Surface Inflammatory Pathologies at the Initiative and Responsibility of the Ophthalmologist.

The purpose of the study was to evaluate the efficacy and safety of systemic mycophenolate mofetil (MMF) treatment in ocular surface inflammatory diseases. For this retrospective study, patients who were treated with systemic MMF for ocular surface inflammatory diseases between March 2020 and March 2022 were evaluated. Apart from demographic data, examination notes including MMF treatment indication and systemic side effect interrogation and routine laboratory examinations during drug treatment were extracted from the patient records. Detailed staging scores were performed according to the diagnosis including Foster and Mondino for ocular mucous membrane pemphigoid (MMP) and limbal stem cell deficiency scoring for limbal transplantation. For thorough evaluation, anterior segment pictures were used. Fourteen patients were enrolled to the study, with a mean age of 58 ± 12. MMP (6, 42.8%) and limbal allograft transplantation (6, 42.8%) constituted the main indications for the MMF treatment, followed by keratitis-ichthyosis-deafness (KID) syndrome (1, 7.2%) and Mooren's ulcer (1, 7.2%). Five of six patients with MMP regressed according to both staging systems. Only one remained stable which was evaluated as Stage 3. Furthermore, while all limbal transplant groups (6) stabilized and showed regression according to the individualized limbal stem cell deficiency staging system with no rejection during follow-up. Furthermore, patients with Mooren's ulcer and KID syndrome showed control of the inflammation and stabilization after MMF treatment. No significant systemic side effects apart from constipation and nausea (3) were observed in patients whose routine laboratory tests were stable throughout the follow-up. MMF has the potential to be a valuable and safe systemic agent of first choice in the control of ocular surface inflammatory disorders, especially when topical treatment is not effective. With such studies, it is predicted that MMF may reach wider usage areas with the increase in its effectiveness and safety in its use for ocular surface inflammatory pathologies.

Is it time to Assess Neurological Status Before Surgery to Improve Postoperative Outcomes?

Is it time to Assess Neurological Status Before Surgery to Improve Postoperative Outcomes?

Use of Defibrotide in Patients with COVID-19 Pneumonia; Results of the Defi-VID19 Phase 2 Trial

Background: The clinical spectrum of COVID-19 ranges from pauci-symptomatic forms to severe disease characterized by respiratory failure requiring mechanical ventilation and intensive care unit (ICU) management, as well as multisystem involvement characterized by sepsis, organ dysfunction and death. Treatment of COVID-19 is not standardized, and respiratory failure from ARDS is the leading cause of mortality; in-hospital mortality at 28-days in our tertiary care center in Lombardia, northern Italy was 23% during the first wave in 2020(Ciceri et al. 2020). Endothelial damage and thrombo-inflammation have been identified as common to both COVID-19 pathophysiology and veno-occlusive disease (VOD/SOS). Defibrotide (DF) has endothelial-protective properties, with pro-fibrinolytic, anti-thrombotic, anti-ischemic, anti-inflammatory, and anti-adhesive activity, but no significant systemic anticoagulant effects and is approved for the treatment of severe VOD/SOS.Aim: A prospective, multicenter, phase II, single-arm, open label trial (DEFI-VID19, NCT04335201) was conducted in patients (pts) with COVID-19 ARDS to evaluate the efficacy of DF in addition to best available therapy per institutional guidelines. The primary endpoint was respiratory-failure rate (RFR) defined as progression of respiratory failure, i.e. severe gas transfer deficit (PaO2/FiO2<200 mmHg), need of ICU or death at day+14 from treatment start. Secondary endpoints included overall survival (OS) at 28 days, duration of hospitalization and safety.A sample size of 50 pts was calculated to detect an absolute reduction of 20% in RFR at day+14, assuming a failure rate in non-treated pts of 70% (alpha=5%, power=90%, two-sided test). Pts received DF intravenously at 6.25 mg/kg/dose by 2-hour infusion repeated every 6 hours. Expected treatment duration was 14 days, with earlier discontinuation if clinical improvement occurred. LMWH at prophylactic dose was allowed. Approval was provided by the National IRB for COVID-19 trials at Institute Spallanzani (Rome) and by the Italian Agency for Drug (AIFA). All patients provided written informed consent.Results: Overall, 52 pts were enrolled from September 2020 to April 2021; 48 were evaluated for efficacy and safety; 4 pts were excluded due to screen failure (n=2) or withdrawal of informed consent at day 2 after defibrotide was initiated (n=2). Median age was 60.5 years (range 53-71); 35 pts (73%) were male and 65% had comorbidities, with high blood pressure, obesity and COPD most common. Two pts had pre-existing diagnoses of non-Hodgkin lymphoma. Median time from onset of COVID-19 symptoms and from Sars-COV2 PCR by nasal swab to enrollment were 8 (range 7-10) and 3 days (range 1-6), respectively. All pts were hospitalized and scale 5 of 8-category ordinal scale by WHO criteria, requiring noninvasive ventilation with CPAP or high-flow oxygen, with a median P/F ratio of 211 (range 134-275) mmHg. At treatment start, the median and (range) lymphocyte counts, LDH, CRP, ferritin, D-dimer and IL-6 were 0.7 (0.5-0.9) x 10e9/L; 404 (291-491) U/L; 49 (22-97) mg/L; 823 (363-1088) ng/ml; 0.44 (0.28-1.29) µg/mL and 20 (11-32), respectively.Median treatment duration was 8.5 days (range 6-11). Overall, 13/48 pts (27%) discontinued the treatment due to clinical worsening and/or need of further therapies: 9 pts experienced progressive respiratory failure and 6 of those were transferred to ICU for IOT (one pt required ECMO), and 4 required full anticoagulation due to pulmonary embolism (n=1), ischemic stroke (n=1), and femoral deep venous thrombosis (n=2). All pts who completed the treatment 35/48 (73%) were discharged with no need of oxygen support. Overall, 14 SAEs have been reported in a median time of 6 days (range 2-10): all unrelated to DF. No pts experienced hemorrhagic events. The incidence of RFR at day 14 was 25 (+/- 6)%, and at day 28, 27 (+/- 6) %. Probability of OS at day 28 was 89 (+/-4) %, at day 60 83 (+/- 5)%. Overall, 8 pts died from COVID-19 -related complications. No pts required re-admission after hospital discharge (median 14 days) or died after discharge.Conclusion: Treatment with DF in pts with grade 5 WHO COVID 19 ARDS does not induce bleeding, and is associated with rapid restoration of respiratory function (73% of pts). Notably, no oxygen support was needed at discharge and a 1-month OS rate of 89% was observed, which is higher than historical controls (77%) treated in the same setting. DisclosuresRichardson: Takeda: Consultancy, Research Funding; AbbVie: Consultancy; Karyopharm: Consultancy, Research Funding; AstraZeneca: Consultancy; Oncopeptides: Consultancy, Research Funding; Jazz Pharmaceuticals: Consultancy, Research Funding; Protocol Intelligence: Consultancy; Secura Bio: Consultancy; Regeneron: Consultancy; Celgene/BMS: Consultancy, Research Funding; GlaxoSmithKline: Consultancy; Janssen: Consultancy; Sanofi: Consultancy. Ciceri: IRCCS Ospedale San Raffaele: Current Employment. Carlo-Stella: Incyte: Honoraria; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Consultancy, Research Funding; AstraZeneca: Honoraria; Celgene: Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen Oncology: Honoraria; Karyopharm Therapeutics: Membership on an entity's Board of Directors or advisory committees.

An Association Between Different Doses of Inhaled Corticosteroids and Glycaemic Status in Patients with Chronic Obstructive Pulmonary Disease

Introduction: Inhaled corticosteroids effective medications for the treatment of asthma. Higher doses of inhaled fluticasone (1000 μgm / day) are commonly used in COPD. Such high doses have been associate with significant systemic effects such as pneumonia, glaucoma, cataracts, adrenal suppression and accelerated bone turnover. Aim of the study: The aim of the study was to evaluate the association between different doses of inhaled corticosteroids (Fluticasone Propionate µgm / day) and glycaemic status in Patients with Chronic Obstructive Pulmonary Disease. Material & Methods: This was a cross-sectional analytical study. This study was conducted at the department of Internal Medicine in Bangobandhu Sheikh Mujib Medical University (BSMMU), Dhaka, Bangladesh, during May, 2016-April, 2017. The protocol of this study was approved by IRB and ethical committee. A total of 80 patients with COPD were included in this study, of them clinically diagnosed 40 consecutive COPD patients who were receiving both bronchodilator & inhaled corticosteroids were recruited as case group and clinically diagnosed 40 consecutive COPD patients receiving only bronchodilator without inhaled corticosteroid/systemic steroid were recruited as control, group. Spirometry was done for confirmation and staging of COPD according to GOLD at indoor and OPD patients of Department of Internal Medicine, BSMMU. Results: In case group, the inhaled corticosteroid dose (5000) was counted 02 (5%) and the mean of FPG value was 6.25±1.34, the inhaled corticosteroid dose (1000) was counted 27 (67.5%) and the mean of FPG value was 5.7±1.58, the inhaled corticosteroid dose (2000) was counted 11 (27.5%) and the mean of FPG value was 6.58±2.24. The total FPG mean of the doses was 5.97±1.78. Among case group according to inhaled corticosteroid dose in case group, the inhaled corticosteroid dose (500) was counted 02 (5%) and the mean of 2HABF value was 9.65±3.18, the inhaled corticosteroid dose (1000) was counted 27 (67.5%) and the mean of 2HABF value was 8.71±2.84, the inhaled corticosteroid dose (2000) was counted 11 (27.5%) and the mean of 2HABF value was 9.51±2.9. The total mean of 2HABF value of the doses was 8.98±2.82. In case group, the inhaled corticosteroid dose (500) was counted 02 (5%) and the mean of HbA1C value was 5.85±1.06, the inhaled corticosteroid dose (1000) was counted 27 (67.5%) and the mean of HbA1C value was 6.07±0.7, the inhaled corticosteroid dose (2000) was counted 11 (27.5%) and the mean of HbA1C value was 6.7±0.74. The total mean of HbA1C value of the doses was 6.23±0.77. Conclusion: We had found that 32% of cases and 7.5% of control group were diagnosed as diabetic when fasting plasma glucose taken into account, while in case of 2 hours after breakfast plasma sugar the number were 32.5% and 10% respectively and in case of HbA1c the number were 23.5% and 10% respectively.

Preclinical Dose-Escalation Study of ZSJ-0228, a Polymeric Dexamethasone Prodrug, in the Treatment of Murine Lupus Nephritis.

Glucocorticoids (GCs) are widely used in the clinical management of lupus nephritis (LN). Their long-term use, however, is associated with the risk of significant systemic side effects. We have developed a poly(ethylene glycol) (PEG)-based dexamethasone (Dex) prodrug (i.e., ZSJ-0228) and in a previous study, demonstrated its potential therapeutic efficacy in mice with established LN, while avoiding systemic GC-associated toxicity. In the present study, we have employed a dose-escalation design to establish the optimal dose-response relationships for ZSJ-0228 in treating LN and further investigated the safety of ZSJ-0228 in lupus-prone NZB/W F1 mice with established nephritis. ZSJ-0228 was intravenously (i.v.) administered monthly at four levels: 0.5 (L1), 1.0 (L2), 3.0 (L3), and 8.0 (L4) mg/kg/day Dex equivalent. For controls, mice were treated with i.v. saline every 4 weeks. In addition, a group of mice received intraperitoneal injections (i.p.) of Dex every day or i.v. injections of Dex every four weeks. Treatment of mice with LN with ZSJ-0228 dosed at L1 resulted in the resolution of proteinuria in 14% of the mice. Mice treated with ZSJ-0228 dosed at L2 and L3 levels resulted in the resolution of proteinuria in ∼60% of the mice in both groups. Treatment with ZSJ-0228 dosed at L4 resulted in the resolution of proteinuria in 30% of the mice. The reduction and/or resolution of the proteinuria, improvement in renal histological scores, and survival data indicate that the most effective dose range for ZSJ-0228 in treating LN in NZB/W F1 mice is between 1.0 and 3.0 mg/kg/day Dex equivalent. Typical GC-associated side effects (e.g., osteopenia, adrenal glands atrophy, etc.) were not observed in any of the ZSJ-0228 treatment groups, confirming its excellent safety profile.

Efficacy of topical dorzolamide 2% in diabetic cystoid macular edema.

To study the effect of topical dorzolamide 2% on macular thickness reduction in diabetic cystoid macular edema (CME). This was a prospective, non-randomized, open study including eyes with diabetic macular edema (DME). All eyes received topical dorzolamide 2% three times daily for one month. Changes in best-corrected visual acuity (BCVA), and central macular thickness (CMT) by optical coherence tomography) were evaluated at 1wk, 1, and 3mo post-treatment. Ninety-three eyes (84 patients) were included. Mean±SD (logMAR) BCVA improved significantly from 1.08±0.26 pretreatment to 0.66±0.24 at 1mo and 0.87±0.26 at 3mo post-treatment (P<0.001 both). The mean±SD CMT was significantly reduced from 535.27±97.4 µm at baseline to 357.43±125.8 µm at 1mo and 376.23±114.5 µm at 3mo post-treatment (P<0.001 both). No significant ocular or systemic side effects were recorded. Topical dorzolamide 2% results in significant improvement of mean BCVA and reduction of mean CMT at 3mo post-treatment. It can be used as an effective, affordable, and safe therapy for treatment of non-refractory diabetic CME.

The psychobiological links between chronic stress-related diseases, periodontal/peri-implant diseases, and wound healing.

Chronic stress is a relevant disease to periodontal practice, encompassing 25%-28% of the US population (American Psychological Association 2015). While it is well established that chronic psychologic stress can have significant deleterious systemic effects, only in recent decades have we begun to explore the biochemical, microbial, and physiologic impacts of chronic stress diseases on oral tissues. Currently, chronic stress is classified as a "risk indicator" for periodontal disease. However, as the evidence in this field matures with additional clinically controlled trials, more homogeneous data collection methods, and a better grasp of the biologic underpinnings of stress-mediated dysbiosis, emerging evidence suggests that chronic stress and related diseases (depression, anxiety) may be significant contributing factors in periodontal/peri-implant disease progression and inconsistent wound healing following periodontal-related therapeutics. Ideal solutions for these patients include classification of the disease process and de-escalation of chronic stress conditions through coping strategies. This paper also summarizes periodontal/implant-related therapeutic approaches to ensure predictable results for this specific patient subpopulation.

The Efficacy, Safety, and Side Effects of Intrapericardial Triamcinolone Treatment in Children with Post-surgical Pericardial Effusion: A Case Series

Intrapericardial triamcinolone can be used to treat chronic pericardial effusion (PE) in adults; however, pediatric data are lacking. In this case series we aim to evaluate the efficacy, safety, and side effects of intrapericardial triamcinolone in children with PE. The incidence and treatment of post-surgical PE from 2009 to 2019 were determined using the institutional surgical database and electronic patient records. Furthermore, a retrospective analysis of efficacy, safety, and side effects of intrapericardial triamcinolone treatment for chronic post-surgical PE was performed. The incidence of postoperative PE requiring treatment was highest after atrial septal defect (ASD) closure when compared to other types of cardiac surgery (9.7% vs 4.3%). Intrapericardial treatment with triamcinolone resolved pericardial effusion in 3 out of 4 patients. All patients developed significant systemic side effects. Surgical ASD closure is associated with an increased risk of development of PE requiring treatment. Intrapericardial triamcinolone is an effective treatment for chronic postoperative PE in children, but is always associated with significant systemic side effects. Close monitoring and treatment of adrenal insufficiency are mandatory in these cases.

The vicious interplay between disrupted sleep and malignant brain tumors: a narrative review

Malignant brain tumors are among the most aggressive human neoplasms. One of the most common and severe symptoms that patients with these malignancies experience is sleep disruption. Disrupted sleep is known to have significant systemic pro-tumor effects, both in patients with other types of cancer and those with malignant brain lesions. We therefore provide a review of the current knowledge on disrupted sleep in malignant diseases, with an emphasis on malignant brain tumors. More specifically, we review the known ways in which disrupted sleep enables further malignant progression. In the second part of the article, we also provide a theoretical framework of the reverse process. Namely, we argue that due to the several possible pathophysiological mechanisms, patients with malignant brain tumors are especially susceptible to their sleep being disrupted and compromised. Thus, we further argue that addressing the issue of disrupted sleep in patients with malignant brain tumors can, not just improve their quality of life, but also have at least some potential of actively suppressing the devastating disease, especially when other treatment modalities have been exhausted. Future research is therefore desperately needed.

Electrophysiological effects and clinical utility of propafenone in children.

This retrospective case series study sought to describe the safety and clinical effectiveness of propafenone for the control of arrhythmias in children with and without CHD or cardiomyopathy. We reviewed baseline characteristics and subsequent outcomes in a group of 63 children treated with propafenone at 2 sites over a 15-year period Therapy was considered effective if no clinically apparent breakthrough episodes of arrhythmias were noted on the medication. Sixty-three patients (29 males) were initiated on propafenone at a median age of 2.3 years. CHD or cardiomyopathy was noted in 21/63 (33%). There were no significant differences between demographics, clinical backgrounds, antiarrhythmic details, side effect profiles, and outcomes between children with normal hearts and children with CHD or cardiomyopathy. Cardiac depression at the initiation of propafenone was more common amongst children with CHD or cardiomyopathy compared to children with normal hearts. Systemic ventricular function was diminished in 15/63 patients (24%) prior to starting propafenone and improved in 8/15 (53%) of patients once better rhythm control was achieved. Other than one child in whom medication was stopped due to gastroesophageal reflux, no other child experienced significant systemic or cardiac side effects during treatment with propafenone. Propafenone achieved nearly equal success in controlling arrhythmias in both children with normal hearts and children with congenital heart disease or cardiomyopathy (90% versus 86%, p = 0.88). Propafenone is a safe and effective antiarrhythmic medication in children.

Gene Expression Profile in Endothelial Cells: Effects of Defibrotide on Different Functional Pathways

Introduction.Sinusoidal obstruction syndrome/veno-occlusive disease (SOS/VOD) is a potentially life-threatening complication of hematopoietic stem cell transplantation (HSCT). It is characterized by endothelial cell (EC) damage and hepatocellular injury due to chemo- and radio-therapy toxicity, resulting in the local release of pro-inflammatory molecules, cell adhesion activation on endothelial cells and coagulative pathway activation. Fibrinolysis activation produces fibrosis of sinusoids followed by perivascular hepatocyte necrosis and venular occlusion. Defibrotide (DF) consists of a mixture of porcine derived single-stranded phosphodiester oligonucleotides and is efficaciously used in the treatment of SOS/VOD. Various in vivo and in vitro findings demonstrate that DF possesses only minimal anticoagulant activity, with potent antithrombotic and profibrinolytic effects antithrombotic properties, without significant systemic anticoagulant effects. Moreover, DF stimulates sinusoidal endothelium by increasing the availability of proangiogenic factors such as bFGF, protecting them from trypsin digestion. Since the mechanism of action of DF is not completely elucidated, we evaluated its effects on the gene expression of ECs.Methods.Endothelial colony forming cells (ECFCs) were obtained from umbilical cord blood according to the method of Ingram et al.(Blood 2004;104:2752-2760). Confluent ECFCs at passages III to IV were subjected to 6-h exposure to either Interferon γ (20 ng/ml; 3 experiments) or lipopolysaccharide (100 ng/ml, 4 experiments), with or without Defibrotide (100 ng/ml). Total RNA was extracted and reverted with a RT2 First Strand cDNA Kit (SABiociences, Qiagen). Genotype profile of control and treated cells was evaluated using the Human Endothelial Cell Biology“ (PAHS-015Z, SABiociences, Qiagen). Data were analyzed using the RT2 Profiler PCR array data analysis template v3.5 (SABiociences, Qiagen). Relative changes in gene expression were calculated using the Ct (cycle threshold) method.Results. The microarray included 84 genes involved in various pathways, including angiogenesis, cell adhesion, inflammatory response, coagulation and platelet activation, apoptosis, vasoconstriction/vasodilatation. We observed striking different effects of DF depending on the activator used. In particular, LPS treated cells displayed a significant upregulation of several genes, including CCL2, CCL5, CX3CL,TF, IL1B, IL6, endothelial selectin, TNF and VCAM1. DF exposure failed to revert the expression of LPS activated genes at levels comparable with unstimulated cells; nevertheless several genes scarcely expressed in LPS-treated cells were highly expressed in LPS+DF treated cells (Figure 1, upper panel). Similarly, CCL2, CCL5, CX3CL1, endothelial selectin, IL6 and VCAM1 were highly expressed in IFN-γ treated cells, although their expression was significantly lower in IFN-γ+DF treated cells (Figure 1, lower panel).Conclusions. These findings suggest that DF effects might be highly dependent on the specific activation setting. In particular, LPS and IFN-γ use different cell signaling pathways, though their downstream effects might partially overlap. According to our observations, DF effects could be mediated by the prevalent interference with specific signaling pathways more than by the direct modulation of target genes. This hypothesis agrees with experimental evidences indicating that DF is internalized by EC but dos not enter nuclei (Palomo et al. Blood 2016;127:1719-27). In alternative, the contemporary exposure of cells to DF and LPS, might result in their competition for modulating in opposite directions the same pathways, thus hampering the inhibitory effects of DF. This second hypothesis agrees with the evidence that DF attachment on cell membrane is sufficient to elicit its anti-inflammatory effect ((Palomo et al. Blood 2016;127:1719-27). [Display omitted] DisclosuresTeofili:Jazz Pharmaceutical: Research Funding. Orlando:Jazz Pharmaceutical: Research Funding.

Rearing system effects on live weight gain of large white turkeys

The aim of this study was to determine the effect of three production systems on live weight gain (LWG) of white turkeys by repeated measures analysis of variance (ANOVA) and profile analysis. A total of 81 turkey poults were assigned to intensive (7 male and 19 female), semi-intensive (9 male and 19 female) and extensive groups (11 male and 16 female) at one day old. The poults were wing-banded at day 1 after hatching and weighed individually each week through 16 weeks old. The birds were managed similarly through eight weeks old. After that time, the intensive group was fed concentrated feed indoors. The birds of the semi-intensive group had access to pasture for eight hours a day, and received 50% of the concentrated feed that was consumed by the intensive group. The birds in the extensive group were kept outdoors with shade and grazed on pasture, but did not receive concentrated feed. The bi-weekly LWG of the extensive, intensive and semi-intensive groups were 1191.4 g, 990.6 g and 872.1 g, respectively. Through the 16 weeks of the trial, the effects on LWG of production system, age, and interaction of age and production system were highly significant (P &lt;0.01) in the repeated measures ANOVA. The profile analysis also showed highly significant (P &lt;0.01) production system effects and interaction of production system and age on LWG. Scheffe’s test indicated that the intensive, semi-intensive, and extensive treatments differed (P &lt;0.05).

Nanostructured Lipid Carriers Engineered as Topical Delivery of Etodolac: Optimization and Cytotoxicity Studies.

Etodolac (ETD), a nonsteroidal anti-inflammatory drug, exhibits antinflammatory, analgesic, and antipyretic activity. The main type of ETD administration is oral route, which is associated with significant systemic side effects. Nanostructured lipid carriers (NLC), a modern lipid formulation, are non-toxic, biocompatible, can improve the solubility and stability of drugs. Nanostructured lipid carriers (NLC) containing etodolac were prepared by a melt-emulsification and ultrasonication technique. Full factorial design (FFD) was applied to optimize the composition of NLC and their properties such as zeta potential, polidyspersity index, and entrapment efficiency. Formulations consisting of Capryol 90, glicerol monostearate, and Tween 20 displayed particle size below 300 nm, encapsulated drug with efficiency of approximately 87% and prolonged drug release up to 24 h. Stable formulations displayed moderately negative surface charge suggesting their limited ability to interact with skin surface but simultaneously presenting their lower risk to cause cell-membrane disruption. In fact, cytotoxicity assessment using human dermal fibroblasts and human epidermal keratinocytes revealed that etodolac-loaded NLC had no important impact on skin cells viability evaluated in vitro, which might evidence that NLC formulations are safe for dermal delivery. The studies developed were relatively fast and simple, requiring no specialized equipment method to prepare NLC as ETD carriers ensuring better solubility and prolonged drug release.

Foliar Indicators and Sweet Cherry Production Efficiency in Central Leader and Kym Green Bush Training Systems in Chile

ABSTRACT Canopy development and production efficiency variations were evaluated in four sweet cherry (Prunus avium L.) cultivars: ‘Bing’, ‘Lapins’, ‘Sweetheart’ and ‘Regina’, grafted on different vigor rootstocks: ‘Colt’, ‘Cab-6P, ‘Maxma-14’ and ‘Gisela-12’, and conducted in two training systems: Central Leader (CL) and Kym Green Bush (KGB), growing in Chile. Leaf indicators were calculated after tree defoliation. A principal components analysis (PCA) was conducted to select indicators that explain the variation among the combinations. Results showed that leaf size and number varied between different cultivar/rootstock combinations and training systems. By means of two principal components, the model employed could explain 72% of the data variability. The most relevant indicators for the PC1 were: leaf weight per hectare (0.98) and leaf area index (0.97), with a significant training system effect, whereas for the PC2 they were: leaf weight per leaf area (0.85) and production per leaf area (0.72), mainly for productive efficiency. In ‘Lapins’/‘Colt’, the KGB system presented a higher weight and leaf area than CL, with almost double the leaf weight per hectare and leaf area index, due mainly to a 37% leaf area per tree and 20% higher tree number/ha in KGB. However, average production per leaf area reached 0.49 kg m−2, without distinction between training systems.

Surface-engineered smart nanocarrier-based inhalation formulations for targeted lung cancer chemotherapy: a review of current practices

Lung cancer is the second most common and lethal cancer in the world. Chemotherapy is the preferred treatment modality for lung cancer and prolongs patient survival by effective controlling of tumor growth. However, owing to the nonspecific delivery of anticancer drugs, systemic chemotherapy has limited clinical efficacy and significant systemic adverse effects. Inhalation routes, on the other hand, allow for direct delivery of drugs to the lungs in high local concentrations, enhancing their anti-tumor activity with minimum side effects. Preliminary research studies have shown that inhaled chemotherapy may be tolerated with manageable adverse effects such as bronchospasm and cough. Enhancing the anticancer drugs deposition in tumor cells and limiting their distribution to other healthy cells will therefore increase their clinical efficacy and decrease their local and systemic toxicities. Because of the controlled release and localization of tumors, nanoparticle formulations are a viable option for the delivery of chemotherapeutics to lung cancers via inhalation. The respiratory tract physiology and lung clearance mechanisms are the key barriers to the effective deposition and preservation of inhaled nanoparticle formulations in the lungs. Designing and creating smart nanoformulations to optimize lung deposition, minimize pulmonary clearance, and improve cancerous tissue targeting have been the subject of recent research studies. This review focuses on recent examples of work in this area, along with the opportunities and challenges for the pulmonary delivery of smart nanoformulations to treat lung cancers.

Identification of novel CD44v6-binding peptides that block CD44v6 and deliver a pro-apoptotic peptide to tumors to inhibit tumor growth and metastasis in mice.

CD44v6, a splice variant of the cell surface glycoprotein CD44, acts as a co-receptor for c-Met and is upregulated in tumors with high metastatic potential.Methods: We screened a phage-displayed peptide library for peptides that selectively bind to CD44v6-overexpressing cells and exploited them to block CD44v6 and deliver a pro-apoptotic peptide to tumors for cancer therapy.Results: CNLNTIDTC (NLN) and CNEWQLKSC (NEW) peptides bound preferentially to CD44v6-high cells than to CD44v6-low cells. The binding affinities of NLN and NEW to CD44v6 protein were 253 ± 79 and 85 ± 18 nM, respectively. Peptide binding to CD44v6-high cells was inhibited by the knockdown of CD44v6 gene expression and competition with an anti-CD44v6 antibody. A pull-down assay with biotin-labeled peptides enriched CD44v6 from cell lysates. NLN and NEW induced CD44v6 internalization and inhibited hepatocyte growth factor-induced c-Met internalization, c-Met and Erk phosphorylation, and cell migration and invasion. In mice harboring tumors, intravenously administered NLN and NEW homed to the tumors and inhibited metastasis to the lungs. When combined with crizotinib, a c-Met inhibitor, treatment with each peptide inhibited metastatic growth more efficiently than each peptide or crizotinib alone. In addition, KLAKLAKKLAKLAK pro-apoptotic peptide guided by NLN (NLN-KLA) or NEW (NEW-KLA) killed tumor cells and inhibited tumor growth and metastasis. No significant systemic side effects were observed after treatments.Conclusions: These results suggest that NLN and NEW are promising metastasis-inhibiting peptide therapeutics and targeting moieties for CD44v6-expressing metastases.

Role of topical beta blockers in regression of infantile capillary hemangioma.

Objective:To observe efficacy of Timolol maleate 0.5% by topical and surface application in infantile superficial capillary hemangioma of eyelid.Methods: This multi-centered clinical case series was carried out at Ophthalmology Department of Bilawal Medical College and Institute of Ophthalmology, LUMHS, Jamshoro from November 2019 to May 2020. We included 14 subjects. All the patients were subjected to detailed clinical examination. Before starting the topical beta blockers, the enrolled subjects had obtained the expert opinion by pediatrician to rule out any preexisting developmental cardio vascular disease. Topical beta blockers 0.5% drops were thus started with, against the ongoing finding of superficial capillary hemangioma of eyelid.Results:There was significant regression in size of infantile hemangioma after treating with topical timolol maleate 0.5%. We included 14 subjects in this study. Mean±SD age of patients was 4.94. Complete regression was seen in 08 subjects at the end of 12 weeks (64%) while 03 were completely cured at 08 weeks (21%) and 01 patient lost follow up with us. No significant ocular and systemic side effects were noted.Conclusion: Topical timolol maleate 0.5% can be the first-line treatment modality for superficial capillary hemangiomas due to its better safety and efficacy.

Implications and Significance of Methyl Mercury Toxicity and Exposure in Riceand Fish

Rice and fish are staple food items in many cultures and are particularly vulnerable to the accumulation of heavy metals, specifically mercury, when exposed to agricultural contamination via agricultural soils and water sources. These contaminated foods are then consumed by higher organisms up in the food chain, leading to further accumulation of the mercury, a process known as bio-amplification. Mercury is considered to be the most toxic heavy metal due to the fact that it causes significant systemic toxic effects. This commentary discusses the implications and significance of mercury in rice and fish and illustrates the necessity for further research to demonstrate the importance for public awareness and education for prevention of exposure to mercury via fish and rice ingestion.

Systemic dendrimer delivery of triptolide to tumor-associated macrophages improves anti-tumor efficacy and reduces systemic toxicity in glioblastoma

Novel delivery strategies are necessary to effectively address glioblastoma without systemic toxicities. Triptolide is a therapy derived from the thunder god vine that has shown potent anti-proliferative and immunosuppressive properties but exhibits significant adverse systemic effects. Dendrimer-based nanomedicines have shown great potential for clinical translation of systemic therapies targeting neuroinflammation and brain tumors. Here we present a novel dendrimer-triptolide conjugate that specifically targets tumor-associated macrophages (TAMs) in glioblastoma from systemic administration and exhibits triggered release under intracellular and intratumor conditions. This targeted delivery improves phenotype switching of TAMs from pro- towards anti-tumor expression in vitro. In an orthotopic model of glioblastoma, dendrimer-triptolide achieved significantly improved amelioration of tumor burden compared to free triptolide. Notably, the triggered release mechanism of dendrimer-mediated triptolide delivery significantly reduced triptolide-associated hepatic and cardiac toxicities. These results demonstrate that dendrimers are a promising targeted delivery platform to achieve effective glioblastoma treatment by improving efficacy while reducing systemic toxicities.