Repeated Low-Dose Acrolein Triggers Irreversible Lamina Propria Edema in Urinary Bladder, Transient Voiding Behavior and Widening of Eyes to Mechanical Stimuli

Acrolein is a metabolite of cyclophosphamide (CYP), an alkylating agent used for a wide range of benign and malignant diseases. CYP treatments are known to trigger hemorrhagic cystitis in patients and animals. Significant effort has been made to prevent CYP/acrolein-induced cystitis, while still maintaining its therapeutic benefits. As a result, supplementary therapeutic options to mediate the protective role against CYP/acrolein and lower doses of CYP are currently given to targeted patients, as compared to past treatments. There is still a need to further study the effects of the repeated low-dose CYP/acrolein on the pathophysiology of the urinary bladder. In our study, a one-time treatment of acrolein and repeated low-dose acrolein triggered the thickening of the smooth muscle and lamina propria in the urinary bladder of C57BL/6J mice, respectively. The first dose of acrolein did not trigger voiding dysfunction, but the second dose triggered high-volume low-frequency voiding. Interestingly, our new scoring criteria and concurrent behavioral assessment revealed that mice with repeated low-dose acrolein had a wider opening of eyes in response to mechanical stimuli. Our study suggests that clinical symptoms among patients undergoing prolonged low-dose CYP may differ from previously reported symptoms of CYP-induced hemorrhagic cystitis.

Download Full-text

Effect of a Low Dose of Carvedilol on Cyclophosphamide-Induced Urinary Toxicity in Rats—A Comparison with Mesna

Pharmaceuticals ◽

10.3390/ph14121237 ◽

2021 ◽

Vol 14 (12) ◽

pp. 1237

Author(s):

Anna Merwid-Ląd ◽

Piotr Ziółkowski ◽

Marta Szandruk-Bender ◽

Agnieszka Matuszewska ◽

Adam Szeląg ◽

...

Keyword(s):

Side Effects ◽

Urinary Bladder ◽

Kidney Function ◽

Significant Interaction ◽

Low Dose ◽

Asymmetric Dimethylarginine ◽

Hemorrhagic Cystitis ◽

Adma Level ◽

Plasma Adma ◽

Better Than

One of the major side effects of cyclophosphamide (CPX)—an alkylating anticancer drug that is still clinically used—is urotoxicity with hemorrhagic cystitis. The present study was designed to evaluate the ability of carvedilol to protect rats from cyclophosphamide-induced urotoxicity. Rats were injected intraperitoneally (i.p.) with CPX (200 mg/kg) and administered carvedilol (2 mg/kg) intragastrically a day before, at the day and a day after a single i.p. injection of CPX, with or without mesna (40, 80, and 80 mg/kg i.p. 20 min before, 4 h and 8 h after CPX administration, respectively). Pretreatment with carvedilol partly prevented the CPX-induced increase in urinary bladder and kidney index, and completely protects from CPX-evoked alterations in serum potassium and creatinine level, but did not prevent histological alterations in the urinary bladder and hematuria. However, carvedilol administration resulted in significant restoration of kidney glutathione (GSH) level and a decrease in kidney interleukin 1β (IL-1β) and plasma asymmetric dimethylarginine (ADMA) concentrations. Not only did mesna improve kidney function, but it also completely reversed histological abnormalities in bladders and prevented hematuria. In most cases, no significant interaction of carvedilol with mesna was observed, although the effect of both drugs together was better than mesna given alone regarding plasma ADMA level and kidney IL-1β concentration. In conclusion, carvedilol did not counteract the injury caused in the urinary bladders but restored kidney function, presumably via its antioxidant and anti-inflammatory properties.

Download Full-text

Nuclear Envelope Integrity in Health and Disease: Consequences on Genome Instability and Inflammation

International Journal of Molecular Sciences ◽

10.3390/ijms22147281 ◽

2021 ◽

Vol 22 (14) ◽

pp. 7281

Author(s):

Benoit R. Gauthier ◽

Valentine Comaills

Keyword(s):

Nuclear Envelope ◽

Clinical Symptoms ◽

Genome Instability ◽

Chromosomal Rearrangements ◽

Wide Range ◽

Complex Chromosomal Rearrangements ◽

Health And Disease ◽

Dna Release ◽

Sting Pathway ◽

Eukaryote Genome

The dynamic nature of the nuclear envelope (NE) is often underestimated. The NE protects, regulates, and organizes the eukaryote genome and adapts to epigenetic changes and to its environment. The NE morphology is characterized by a wide range of diversity and abnormality such as invagination and blebbing, and it is a diagnostic factor for pathologies such as cancer. Recently, the micronuclei, a small nucleus that contains a full chromosome or a fragment thereof, has gained much attention. The NE of micronuclei is prone to collapse, leading to DNA release into the cytoplasm with consequences ranging from the activation of the cGAS/STING pathway, an innate immune response, to the creation of chromosomal instability. The discovery of those mechanisms has revolutionized the understanding of some inflammation-related diseases and the origin of complex chromosomal rearrangements, as observed during the initiation of tumorigenesis. Herein, we will highlight the complexity of the NE biology and discuss the clinical symptoms observed in NE-related diseases. The interplay between innate immunity, genomic instability, and nuclear envelope leakage could be a major focus in future years to explain a wide range of diseases and could lead to new classes of therapeutics.

Download Full-text

A Phase II Safety and Efficacy Study on Prognosis of Moderate Pneumonia in COVID-19 patients with Regular Intravenous Immunoglobulin Therapy

The Journal of Infectious Diseases ◽

10.1093/infdis/jiab098 ◽

2021 ◽

Author(s):

Raman R S ◽

Vijaykumar Bhagwan Barge ◽

Anil Kumar Darivenula ◽

Himanshu Dandu ◽

Rakesh R Kartha ◽

...

Keyword(s):

Mechanical Ventilation ◽

Randomized Study ◽

Standard Of Care ◽

Immunoglobulin Therapy ◽

Clinical Trial Registry ◽

Open Label ◽

Intravenous Immunoglobulin Therapy ◽

Safety And Efficacy ◽

Therapeutic Benefits ◽

Wide Range

Abstract Background Currently, there is no specific drug for the treatment of COVID-19. Therapeutic benefits of intravenous immunoglobin (IVIG) have been demonstrated in wide range of diseases. The present study is conducted to evaluate the safety and efficacy of IVIG in the treatment of COVID-19 patients with moderate pneumonia. Methods An open-label, multicenter, comparative, randomized study was conducted on COVID-19 patients with moderate pneumonia. 100 eligible patients were randomized in 1:1 ratio either to receive IVIG + standard of care (SOC) or SOC. Results Duration of hospital stay was significantly shorter in IVIG group to that of SOC alone (7.7 Vs. 17.5 days). Duration for normalization of body temperature, oxygen saturation and mechanical ventilation were significantly shorter in IVIG compared to SOC. Percentages of patients on mechanical ventilation in two groups were not significantly different (24% Vs. 38%). Median time to RT-PCR negativity was significantly shorter with IVIG than SOC (7 Vs.18 days). There were only mild to moderate adverse events in both groups except for one patient (2%), who died in SOC. Conclusions IVIG was safe and efficacious as an adjuvant with other antiviral drugs in the treatment of COVID-19. The trial was registered under Clinical Trial Registry, India (CTRI/2020/06/026222).

Download Full-text

A Slot-Die Technique for the Preparation of Continuous, High-Area, Chitosan-Based Thin Films

Polymers ◽

10.3390/polym13101566 ◽

2021 ◽

Vol 13 (10) ◽

pp. 1566

Author(s):

Oliver J. Pemble ◽

Maria Bardosova ◽

Ian M. Povey ◽

Martyn E. Pemble

Keyword(s):

Thin Films ◽

Mechanical Properties ◽

High Volume ◽

Mechanical Anisotropy ◽

Diverse Range ◽

Direction Parallel ◽

High Area ◽

Wide Range ◽

Slot Die ◽

Potential Applications

Chitosan-based films have a diverse range of potential applications but are currently limited in terms of commercial use due to a lack of methods specifically designed to produce thin films in high volumes. To address this limitation directly, hydrogels prepared from chitosan, chitosan-tetraethoxy silane, also known as tetraethyl orthosilicate (TEOS) and chitosan-glutaraldehyde have been used to prepare continuous thin films using a slot-die technique which is described in detail. By way of preliminary analysis of the resulting films for comparison purposes with films made by other methods, the mechanical strength of the films produced was assessed. It was found that as expected, the hybrid films made with TEOS and glutaraldehyde both show a higher yield strength than the films made with chitosan alone. In all cases, the mechanical properties of the films were found to compare very favorably with similar measurements reported in the literature. In order to assess the possible influence of the direction in which the hydrogel passes through the slot-die on the mechanical properties of the films, testing was performed on plain chitosan samples cut in a direction parallel to the direction of travel and perpendicular to this direction. It was found that there was no evidence of any mechanical anisotropy induced by the slot die process. The examples presented here serve to illustrate how the slot-die approach may be used to create high-volume, high-area chitosan-based films cheaply and rapidly. It is suggested that an approach of the type described here may facilitate the use of chitosan-based films for a wide range of important applications.

Download Full-text

Prodromal Dementia With Lewy Bodies: Evolution of Symptoms and Predictors of Dementia Onset

Journal of Geriatric Psychiatry and Neurology ◽

10.1177/08919887211023586 ◽

2021 ◽

pp. 089198872110235

Author(s):

Kathryn A. Wyman-Chick ◽

Lauren R. O’Keefe ◽

Daniel Weintraub ◽

Melissa J. Armstrong ◽

Michael Rosenbloom ◽

...

Keyword(s):

Clinical Features ◽

Dementia With Lewy Bodies ◽

Clinical Symptoms ◽

Neuropsychiatric Symptoms ◽

Lewy Bodies ◽

Rem Sleep Behavior Disorder ◽

Data Set ◽

Wide Range ◽

Prodromal Dementia ◽

Dementia Onset

Background: Research criteria for prodromal dementia with Lewy bodies (DLB) were published in 2020, but little is known regarding prodromal DLB in clinical settings. Methods: We identified non-demented participants without neurodegenerative disease from the National Alzheimer’s Coordinating Center Uniform Data Set who converted to DLB at a subsequent visit. Prevalence of neuropsychiatric and motor symptoms were examined up to 5 years prior to DLB diagnosis. Results: The sample included 116 participants clinically diagnosed with DLB and 348 age and sex-matched (1:3) Healthy Controls. Motor slowing was present in approximately 70% of participants 3 years prior to DLB diagnosis. In the prodromal phase, 50% of DLB participants demonstrated gait disorder, 70% had rigidity, 20% endorsed visual hallucinations, and over 50% of participants endorsed REM sleep behavior disorder. Apathy, depression, and anxiety were common prodromal neuropsychiatric symptoms. The presence of 1+ core clinical features of DLB in combination with apathy, depression, or anxiety resulted in the greatest AUC (0.815; 95% CI: 0.767, 0.865) for distinguishing HC from prodromal DLB 1 year prior to diagnosis. The presence of 2+ core clinical features was also accurate in differentiating between groups (AUC = 0.806; 95% CI: 0.756, 0.855). Conclusion: A wide range of motor, neuropsychiatric and other core clinical symptoms are common in prodromal DLB. A combination of core clinical features, neuropsychiatric symptoms and cognitive impairment can accurately differentiate DLB from normal aging prior to dementia onset.

Download Full-text

Low Dose of Fluoride in the Culture Medium of Cordyceps militaris Promotes Its Growth and Enhances Bioactives with Antioxidant and Anticancer Properties

Journal of Fungi ◽

10.3390/jof7050342 ◽

2021 ◽

Vol 7 (5) ◽

pp. 342

Author(s):

Xiaoshuai Li ◽

Jia Wang ◽

Huayue Zhang ◽

Long Xiao ◽

Zhongfang Lei ◽

...

Keyword(s):

Low Dose ◽

Radical Scavenging ◽

Potassium Fluoride ◽

Cordyceps Militaris ◽

Carotenoid Content ◽

Market Demand ◽

Fruiting Bodies ◽

Human Osteosarcoma Cells ◽

Wide Range ◽

Bioactive Ingredients

Cordyceps militaris possesses several compounds with medicinal properties, and is commonly used in traditional Chinese functional food and medicine for a variety of health benefits. Because of its rare occurrence in nature, the market demand for artificial C. militaris is on the rise. Furthermore, efforts to increase its bioactive ingredients have also been considered in research. In this study, we aimed to investigate the effect of fluoride on the growth and enrichment of bioactive compounds in C. militaris. A wide range of potassium fluoride concentrations (0, 0.001, 0.01, 0.1, and 1 mM) were added to the culture media as a source of fluoride during the cultivation of C. militaris fruiting bodies. The contents of fluorine and bioactive substances of the fruiting bodies in normal (NM) and fluorine-supplemented (FM) media were measured and compared. C. militaris raised in the growth medium supplemented with 0.01 mM potassium fluoride led to a 44.86% (1.55 ± 0.14 g/bottle) increase in biomass and a 23.43% (3161.38 ± 35.71 µg/g) increase in total carotenoid content in the fruiting bodies. Furthermore, a remarkable increase in superoxide dismutase-like activity (84.75 U/mg) and 2,2-diphenyl-1-picrylhydrazyl radical scavenging activity (IC50 = 2.59 mg/mL) was recorded. In human cancer cell-based assays, C. militaris raised in FM caused stronger cytotoxicity, apoptosis, and cell cycle arrest in human osteosarcoma cells. These results demonstrated that a low dose of fluoride could stimulate the growth of C. militaris fruiting bodies and enhance the production of bioactive ingredients that possess useful antioxidant and anticancer activities.

Download Full-text

Characteristics of registered clinical trials assessing treatments for COVID-19: a cross-sectional analysis

BMJ Open ◽

10.1136/bmjopen-2020-039978 ◽

2020 ◽

Vol 10 (6) ◽

pp. e039978 ◽

Cited By ~ 13

Author(s):

Hemalkumar B Mehta ◽

Stephan Ehrhardt ◽

Thomas J Moore ◽

Jodi B Segal ◽

G Caleb Alexander

Keyword(s):

Clinical Trials ◽

Clinical Investigation ◽

Scientific Progress ◽

Cross Sectional ◽

Design Elements ◽

Cross Sectional Analysis ◽

Therapeutic Benefits ◽

Wide Range ◽

The Usa ◽

Sectional Analysis

ObjectivesThe coronavirus disease 2019 (COVID-19) pandemic has prompted many initiatives to identify safe and efficacious treatments, yet little is known regarding where early efforts have focused. We aimed to characterise registered clinical trials assessing drugs or plasma treatments for COVID-19.Design, setting and participantsCross-sectional analysis of clinical trials for the treatment of COVID-19 that were registered in the USA or in countries contributing to the WHO’s International Clinical Trials Registry Platform. Relevant trial entries of drugs or plasma were downloaded on 26 March 2020, deduplicated, verified with reviews of major medical journals and WHO websites and independently analysed by two reviewers.Main outcome(s)Trial intervention, sponsorship, critical design elements and specified outcomesResultsOverall, 201 clinical trials were registered for testing the therapeutic benefits of 92 drugs or plasma, including 64 in monotherapy and 28 different combinations. Only eight (8.7%) products or combinations involved new molecular entities. The other test therapies had a wide range of prior medical uses, including as antivirals, antimalarials, immunosuppressants and oncology treatments. In 152 trials (75.7%), patients were randomised to treatment or comparator, including 55 trials with some form of blinding and 97 open-label studies. The 49 (24.4%) of trials without a randomised design included 29 single armed studies and 20 trials with some comparison group. Most trial designs featured multiple endpoints. Clinical endpoints were identified in 134 (66.7%) of trials and included COVID-19 symptoms, death, recovery, required intensive care and hospital discharge. Clinical scales were being used in 33 (16.4%) trials, most often measures of oxygenation and critical illness. Surrogate endpoints or biomarkers were studied in 88 (42.3%) of trials, primarily assays of viral load. Although the trials were initiated in more than 17 countries or regions, 100 (49.8%) were registered in China and 78 (37.8%) in the USA. Registered trials increased rapidly, with the number of registered trials doubling from 1 March to 26 March 2020.ConclusionsWhile accelerating morbidity and mortality from the COVID-19 pandemic has been paralleled by early and rapid clinical investigation, many trials lack features to optimise their scientific value. Global coordination and increased funding of high-quality research may help to maximise scientific progress in rapidly discovering safe and effective treatments.

Download Full-text

Surgical Management of Neuroendocrine Tumours of the Pancreas

Journal of Clinical Medicine ◽

10.3390/jcm9092993 ◽

2020 ◽

Vol 9 (9) ◽

pp. 2993

Author(s):

Regis Souche ◽

Christian Hobeika ◽

Elisabeth Hain ◽

Sebastien Gaujoux

Keyword(s):

Neuroendocrine Tumours ◽

Islet Cells ◽

Preoperative Evaluation ◽

High Volume ◽

Genetic Syndromes ◽

Active Peptides ◽

Wide Range ◽

Precise Diagnosis ◽

Short And Long Term ◽

Open Versus

Neuroendocrine tumours of the pancreas (pNET) are rare, accounting for 1–2% of all pancreatic neoplasms. They develop from pancreatic islet cells and cover a wide range of heterogeneous neoplasms. While most pNETs are sporadic, some are associated with genetic syndromes. Furthermore, some pNETs are ‘functioning’ when there is clinical hypersecretion of metabolically active peptides, whereas others are ‘non-functioning’. pNET can be diagnosed at a localised stage or a more advanced stage, including regional or distant metastasis (in 50% of cases) mainly located in the liver. While surgical resection is the cornerstone of the curative treatment of those patients, pNET management requires a multidisciplinary discussion between the oncologist, radiologist, pathologist, and surgeon. However, the scarcity of pNET patients constrains centralised management in high-volume centres to provide the best patient-tailored approach. Nonetheless, no treatment should be initiated without precise diagnosis and staging. In this review, the steps from the essential comprehensive preoperative evaluation of the best surgical approach (open versus laparoscopic, standard versus sparing parenchymal pancreatectomy, lymphadenectomy) according to pNET staging are analysed. Strategies to enhance the short- and long-term benefit/risk ratio in these particular patients are discussed.

Download Full-text

Agenesis of Isthmus of the Thyroid Gland in a Patient with Graves-Basedow Disease and a Solitary Nodule

Case Reports in Surgery ◽

10.1155/2013/608481 ◽

2013 ◽

Vol 2013 ◽

pp. 1-2

Author(s):

Omer Faruk Ozkan ◽

Mehmet Asık ◽

Huseyin Toman ◽

Faruk Ozkul ◽

Oztekin Cıkman ◽

...

Keyword(s):

Congenital Anomaly ◽

Thyroid Gland ◽

Surgical Procedures ◽

Congenital Anomalies ◽

Clinical Symptoms ◽

Endocrine Gland ◽

Solitary Nodule ◽

Rare Congenital Anomaly ◽

Wide Range

The thyroid is a vascular endocrine gland with two lateral lobes connected by a narrow, median isthmus. Although a wide range of congenital anomalies of the thyroid gland has been reported in the literature, agenesis of the thyroid isthmus is a very rare congenital anomaly. Thyroid isthmus agenesis does not manifest clinical symptoms, and it can be confused with other thyroid pathologies. We describe a patient with no isthmus of the thyroid, associated with Graves-Basedow disease. Thyroid isthmus agenesis should be kept in mind in order for surgical procedures involving thyroid pathologies to be carried out safely.

Download Full-text

Insights into Clinical, Genetic, and Pathological Aspects of Hereditary Spastic Paraplegias: A Comprehensive Overview

Frontiers in Molecular Biosciences ◽

10.3389/fmolb.2021.690899 ◽

2021 ◽

Vol 8 ◽

Author(s):

Liena E. O. Elsayed ◽

Isra Zuhair Eltazi ◽

Ammar E. Ahmed ◽

Giovanni Stevanin

Keyword(s):

Clinical Symptoms ◽

Disease Onset ◽

Lower Limbs ◽

Special Focus ◽

Clinical Genetic ◽

Comprehensive Overview ◽

Functional Studies ◽

Hereditary Spastic Paraplegias ◽

Wide Range ◽

Complex Forms

Hereditary spastic paraplegias (HSP) are a heterogeneous group of motor neurodegenerative disorders that have the core clinical presentation of pyramidal syndrome which starts typically in the lower limbs. They can present as pure or complex forms with all classical modes of monogenic inheritance reported. To date, there are more than 100 loci/88 spastic paraplegia genes (SPG) involved in the pathogenesis of HSP. New patterns of inheritance are being increasingly identified in this era of huge advances in genetic and functional studies. A wide range of clinical symptoms and signs are now reported to complicate HSP with increasing overall complexity of the clinical presentations considered as HSP. This is especially true with the emergence of multiple HSP phenotypes that are situated in the borderline zone with other neurogenetic disorders. The genetic diagnostic approaches and the utilized techniques leave a diagnostic gap of 25% in the best studies. In this review, we summarize the known types of HSP with special focus on those in which spasticity is the principal clinical phenotype (“SPGn” designation). We discuss their modes of inheritance, clinical phenotypes, underlying genetics, and molecular pathways, providing some observations about therapeutic opportunities gained from animal models and functional studies. This review may pave the way for more analytic approaches that take into consideration the overall picture of HSP. It will shed light on subtle associations that can explain the occurrence of the disease and allow a better understanding of its observed variations. This should help in the identification of future biomarkers, predictors of disease onset and progression, and treatments for both better functional outcomes and quality of life.

Download Full-text