Αρχειοθήκη ιστολογίου

Τρίτη 27 Απριλίου 2021

Chronic administration of pharmacological doses of angiotensin 1-7 and iodoangiotensin 1-7 has minimal effects on blood pressure, heart rate, and cognitive function of spontaneously hypertensive rats

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Physiol Rep. 2021 Apr;9(7):e14812. doi: 10.14814/phy2.14812.

ABSTRACT

Cardiovascular diseases are the principal cause of death worldwide, with hypertension being the most common cardiovascular disease risk factor. High blood pressure (BP) is also associated with an increased risk of poor cognitive performance and dementia including Alzheimer's disease. Angiotensin 1-7 (Ang 1-7), a product of the renin-angiotensin system (RAS), exhibits central and peripheral actions to reduce BP. R ecent data from our lab reveals that the addition of a non-radioactive iodine molecule to the tyrosine in position 4 of Ang 1-7 (iodoAng 1-7) makes it ~1000-fold more potent than Ang 1-7 in competing for the 125 I-Ang 1-7 binding site (Stoyell-Conti et al., 2020). Moreover, the addition of the non-radioactive iodine molecule increases (~4-fold) iodoAng 1-7's ability to bind to the AT1 receptor (AT1R), the primary receptor for Ang II. Preliminary data indicates that iodoAng 1-7 can also compete for the 125 I-Ang IV binding site with a low micromolar IC50. Thus, our aims were to compare the effects of chronic treatment of the Spontaneously Hypertensive Rat (SHR) with iodoAng 1-7 (non-radioactive iodine isotope) and Ang 1-7 on arterial pressure, heart rate, and cognitive function. For this study, male SHRs were divided into three groups and treated with Saline, Ang 1-7, or iodoAng 1-7 administrated subcutaneously using a 28-day osmotic mini pump. Systolic BP was m easured non-invasively by the tail-cuff technique. Cognitive function was assessed by Y-Maze test and novel object recognition (NOR) test. We have demonstrated in SHRs that subcutaneous administration of high doses of iodoAng 1-7 prevented the increase in heart rate with age, while Ang 1-7 showed a trend toward preventing the increase in heart rate, possibly by improving baroreflex control of the heart. Conversely, neither Ang 1-7 nor iodoAng 1-7 administered subcutaneously affected BP nor cognitive function.

PMID:33904655 | DOI:10.14814/phy2.14812

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Increasing prediction accuracy of pathogenic staging by sample augmentation with a GAN

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by ChangHyuk Kwon, Sangjin Park, Soohyun Ko, Jaegyoon Ahn

Accurate prediction of cancer stage is important in that it enables more appropriate treatment for patients with cancer. Many measures or methods have been proposed for more accurate prediction of cancer stage, but recently, machine learning, especially deep learning-based methods have been receiving increasing attention, mostly owing to their good prediction accuracy in many applications. Machine learning methods can be applied to high throughput DNA mutation or RNA expression data to predict cancer stage. However, because the number of genes or markers generally exceeds 10,000, a considerable number of data samples is required to guarantee high prediction accuracy. To solve this problem of a small number of clinical samples, we used a Generative Adversarial Networks (GANs) to augment the samples. Because GANs are not effective with whole genes, we first selected significant genes using DNA mutation data and random forest feature ranking. Next, RNA expression data for selected genes were expanded using GANs. We compared the classification accuracies using original dataset and expanded datasets generated by proposed and existing methods, using random forest, Deep Neural Networks (DNNs), and 1-Dimensional Convolutional Neural Networks (1DCNN). When using the 1DCNN, the F1 score of GAN5 (a 5-fold increase in data) was improved by 39% in relation to the original data. Moreover, the results using only 30% of the data were better than those using all of the data. Our attempt is the first to use GAN for augmentation using numeric data for both DNA and RNA. The augmented datasets obtained using the proposed method demonstrated significantly increased classification accuracy for most cases. By using GAN and 1DCNN in the prediction of cancer stage, we confirmed that good results can be obtained even with small amounts of samples, and it is expected that a great deal of the cost and time required to obtain clinical samples will be reduced. The proposed sample augmentatio n method could also be applied for other purposes, such as prognostic prediction or cancer classification.
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Die Behandlung von Schilddrüsenmalignomen aus HNO-ärztlicher Sicht

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Laryngorhinootologie
DOI: 10.1055/a-1475-4939

Einleitung Die Zahl der Schilddrüsenmalignome zeigt eine deutliche Zunahme. Da die Schilddrüse an der HNO-Klinik Bad Hersfeld im Fokus steht, war dies für uns Anlass, unsere Behandlungsresultate zu untersuchen und Erfahrungen darzustellen. Material und Methoden Es handelt sich um eine Untersuchung beginnend im Jahre 2014 bis zum Juli 2020. Es wurden alle Patienten mit Schilddrüsenmalignomen erfasst und wichtige demografische und medizinische Parameter wie Alter, Geschlecht, Histologie, Calcium, OP-Dauer, Rekurrensparese etc. registriert. Ergebnisse Es wurden insgesamt 63 Patienten mit malignen Schilddrüsenerkrankungen eingeschlossen. Davon waren 42 weiblichen und 21 männlichen Geschlechts. Die Altersspanne reichte von 11 bis zu 95 Jahren. Patienten mit differenzierten Schilddrüsenkarzinomen waren im Schnitt jünger als diejenigen mit anaplastischen Malignomen. Histologisch dominierten die papillären Schilddrüsenkarzinome mit 65 % (n = 41) gegenüber anderen Varianten wie dem follikulären (n = 6), medullären (n = 5) und entdifferenzierten Karzinom (n = 6). Alle Patienten wurden einer operativen Behandlung unterzogen; postoperativ erhielten die Betroffenen mit fortgeschrittenen, differenzierten Karzinomen eine Radiojodtherapie. Von den Patienten mit einem entdifferenzierten Karzinom sind alle ihrem Leiden erlegen, während nach unserer Kenntnis nur eine Betroffene mit einem differenzierten Malignom tumorbedingt verstorben ist. Schlussfolgerung In die Behandlung von malignen Schilddrüsenerkrankungen ist der HNO-Arzt eingebunden. Wie bei den benignen Erkrankungen der endokrinen Halsorgane ist eine interdisziplinäre Zusammenarbeit entscheidend.
[...]

Georg Thieme Verlag KG Rüdigerstraße 14, 70469 Stuttgart, Germany

Article in Thieme eJournals:
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Dermatomyositis als paraneoplastisches Syndrom bei Kopf-Hals-Malignomen: Fallserie & Literaturreview

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Laryngorhinootologie
DOI: 10.1055/a-1408-6551

Einleitung/Ziel Die Dermatomyositis (DM) ist eine seltene Erkrankung, die sich klinisch durch Schwäche und Schmerzen proximaler Muskeln sowie fliederfarbene Hautveränderungen manifestiert. In fast einem Fünftel der Fälle ist die DM mit dem Auftreten von Tumorerkrankungen assoziiert. Ziel dieser Untersuchung ist die Bewertung der Bedeutung der DM als paraneoplastisches Syndrom bei Malignomen im Kopf-Hals-Bereich unter Berücksichtigung der aktuellen Literatur. Material/Methoden Nach retrospektiver Krankenaktenanalyse der Jahre 2008–2018 von Patienten mit Kopf-Hals-Malignomen fanden sich 8 Patienten mit einer Dermatomyositis: 4 Patienten mit Tonsillenkarzinom, 1 Patient mit Nasopharynxkarzinom, 1 Patient mit Parotiskarzinom und 2 Patienten mit Lymphomen. Es wurden die Diagnostik, Therapie und Behandlungsergebnisse der Fälle beschrieben. Zudem erfolgte eine selektive Analyse der Literatur (PubMed) zur DM bei HNO-Tumoren. Bei dieser fanden sich insgesamt 290 Fälle: die Malignome waren in 283 Fällen im Nasopharynx, in 5 Fällen in der Tonsille und in 2 Fällen im Hypopharynx lokalisiert. Ergebnisse/Schlussfolgerung Eine DM als paraneoplastisches Syndrom bei Kopf-Hals-Malignomen ist selten. Sie tritt häufiger in Assoziation mit Nasopharynxkarzinomen und selten bei Tonsillenkarzinomen auf.Das gehäufte Auftreten der DM bei Kopf-Hals-Malignomen in Abhängigkeit von der ethnischen Verteilung (Nasopharynxkarzinome – asiatische Abstammung, Tonsillenkarzinom – kaukasische Abstammung) ist möglicherweise auch auf regionale Inzidenzunterschiede der genannten Tumorentitäten zurückzuführen.Bei Patienten mit einer DM sollte ein Tumorausschluss auch im Kopf-Hals-Bereich erfolgen, insbesondere bei Vorliegen einer zervikalen Lymphadenopathie. Der Verlauf einer tumorassoziierten DM wird durch die Tumortherapie positiv beeinflusst. Therapeutisch ist aber auch eine konsequente Behandlung der DM die Grundlage für eine erfolgreiche Tumortherapie.
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Georg Thieme Verlag KG Rüdigerstraße 14, 70469 Stuttgart, Germany

Article in Thieme eJournals:
Table of contents  |  Abstract  |  Full text

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Revision canal-wall down surgery: comparison of surgical outcomes with three different techniques

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Eur Arch Otorhinolaryngol. 2021 Apr 27. doi: 10.1007/s00405-021-06829-y. Online ahead of print.

ABSTRACT

OBJECTIVE: This study aimed to analyze the role of the endoscope in revision canal-wall down (CWD) tympanomastoid surgery and compare its use to the more traditional microscopic approach. Moreover, we aim to investigate functional outcomes of revision surgeries in a cohort of two tertiary reference centers.

METHODS: A total of 103 patients undergoing revision surgery after previous CWD tympanomastoidectomy were included in the present study and divided in three groups according to the surgical technique used: endoscope exclusive (n = 22), combined (n = 35) and microscope exclusive (n = 46). Data regarding surgical indications, pre-operative clinical and audiological assessments, intraoperative findings and surgical considerations were extracted. During follow-up, data regarding anatomic and audiologic outcomes were collected a nd persistence or recurrence of the disease assessed.

RESULTS: The most frequent sites of cholesteatoma recurrence or persistence was the anterior epitympanum. There was a statistically significant ABG improvement of - 6.02 dB HL (95% CI - 8.87 to - 3.16, p < 0.001) between pre-operative and postoperative ABG, without significant effect of surgical technique. During follow-up, no significant differences regarding disease or otorrhea control were observed. Duration of surgery and hospitalization was shorter in the endoscopic cohort without statistical significance. Intra- and postoperative complications were lower in the endoscopic group.

CONCLUSION: Revision CWD surgery can take advantage of the endoscope as a minimally invasive exclusive or adjunct tool to traditional microscopic procedures. Outcome measures of endoscopic revision CWD surgery showed anatomic and functional results comparable to those of the microscopic group. The complication rate, the duration of su rgery and hospitalization were favorable in the endoscopic group.

PMID:33904981 | DOI:10.1007/s00405-021-06829-y

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Δευτέρα 26 Απριλίου 2021

Dual mTORC1/mTORC2 inhibition as a Host-Directed Therapeutic Target in Pathologically Distinct Mouse Models of Tuberculosis [Experimental Therapeutics]

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Efforts to develop more effective and shorter-course therapies for tuberculosis have included a focus on host-directed therapy (HDT). The goal of HDT is to modulate the host response to infection, thereby improving immune defenses to reduce the duration of antibacterial therapy and/or the amount of lung damage. As a mediator of innate and adaptive immune responses involved in eliminating intracellular pathogens, autophagy is a potential target for HDT in tuberculosis. Because Mycobacterium tuberculosis modulates mammalian target of rapamycin (mTOR) signaling to impede autophagy, pharmacologic mTOR inhibition could provide effective HDT. mTOR exists within two distinct multiprotein complexes, mTOR complex-1 (mTORC1) and mTOR complex-2 (mTORC2). Rapamycin and its analogs only partially inhibit mTORC1. We hypothesized that novel mTOR kinase inhibitors blocking both complexes would have expanded therapeutic potential. We compared the effects of two mTOR inhibitors: rapamycin and the orally available mTOR kinase domain inhibitor CC214-2, which blocks both mTORC1 and mTORC2, as adjunctive therapies against murine TB, when added to the first-line regimen (RHZE) or the novel bedaquiline-pretomanid-linezolid (BPaL) regimen. Neither mTOR inhibitor affected lung CFU counts after 4-8 weeks of treatment when combined with BPaL or RHZE. However, addition of CC214-2 to BPaL and RHZE was associated with significantly fewer relapses in C3HeB/FeJ compared to addition of rapamycin and, in RHZE-trea ted mice, resulted in fewer relapses compared to RHZE alone. Therefore, CC214-2 and related mTOR kinase inhibitors may be more effective candidates for HDT than rapamycin analogs and may have the potential to shorten the duration of TB treatment.

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In Vitro Activity of Oxazolidinone against Nontuberculous Mycobacteria, Including Macrolide-Resistant Clinical Isolates [Susceptibility]

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We evaluated the in vitro activities of oxazolidinone antibiotics including linezolid, sutezolid, and delpazolid against clinical nontuberculous mycobacteria isolates. Regardless of macrolide resistance, for M. avium, M. intracellulare, and M. kansasii, sutezolid showed the lowest minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) value among oxazolidinone antibiotics. However, for M. abscessus, M. massiliense, the MIC and MBC values fo r all oxazolidinone antibiotics showed similar values. Oxazolidinone antibiotics warrant further investigation as potential antibiotics.

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Multidrug Resistance Efflux Pumps in Acinetobacter spp.: An Update [Minireviews]

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Acinetobacter spp. have become of increased clinical importance as studies have shown the antimicrobial resistant potential of these species. Efflux pumps can lead to reduced susceptibility to a variety of antibiotics and are present in large number across Acinetobacter spp. There are six families of efflux pumps that have been shown to be of clinical relevance: the Major Facilitator Superfamily (MFS), Small Multidrug Resistance (SMR) family, ATP-binding cassette (ABC) family, Multidrug and Toxi c Compound Extrusion (MATE) family, Proteobacterial Antimicrobial Compound Efflux (PACE) family and Resistance-Nodulation-Division (RND) family. A lot of work has been done on understanding and characterizing the roles that these efflux pumps play in relation to antimicrobial resistance and the physiology of these bacteria. RND efflux pumps, with their expansive substrate profiles, are a major component of Acinetobacter spp. antimicrobial resistance. New discoveries over the last decade have shed a lot of light on to the complex regulation of these efflux pumps leading to greater understanding and potential of slowing the reduced susceptibility seen by these bacterial species.

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Luminore CopperTouch™ surface coating effectively inactivates SARS-CoV-2, Ebola and Marburg in vitro [Antiviral Agents]

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We investigated the ability of Luminore CopperTouchTM copper and copper–nickel surfaces to inactivate filoviruses and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The copper and copper–nickel surfaces inactivated 99.9% of Ebola and Marburg viruses after 30 minutes and the copper surfaces inactivated 99% of SARS-CoV-2 in 2 hours. These data reveal that Ebolavirus, Marburgvirus, and SARS-CoV-2 are inactivated by exposure to copper ions, validating Luminore CopperTouchTM as an efficacious tool for infection control.

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Quinolin-(1H)-imines as a new chemotype against leishmaniasis: biological evaluation and mechanistic studies [Mechanisms of Action]

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Leishmaniasis is one of the most challenging neglected tropical diseases and remains a global threat to public health. Currently available therapies for leishmaniases present significant drawbacks and are rendered increasingly inefficient due to parasite resistance, urging the need for more effective, safer, and cheaper drugs. In our efforts to identify novel chemical scaffolds for the development of antileishmanial agents, we have screened in house antiplasmodial libraries against axenic and intracellular fo rms of Leishmania infantum, L. amazonensis and L. major. Several of the screened compounds showed IC50 values against intracellular L. infantum parasites in the submicromolar range (1h: IC50 0.9 μM and 1n: IC50 0.7 μM) and selectivity indexes of 11 and 9.7, respectively. Compounds also displayed activity against L. amazonensis and L. major, albeit in the low micromolar range. Mechanistic studies revealed that 1n efficiently inhibits oxygen consumption and significantly decreases the mitochondrial membrane potential in L. infantum axenic amastigotes, suggesting that this chemotype acts, at least in part, by interfering with mitochondrial function. Structure-activity analysis suggests that 1n is a promising antileishmanial lead and emphasize the potential of the quinoline-(1H)-imine chemotype for the future development of new antileishmanial agents.

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Melting the Eis: non-detection of kanamycin resistance markers by routine diagnostic tests and identification of new eis-promoter variants [Mechanisms of Resistance]

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Eis-promoter mutations can confer reduced Mycobacterium tuberculosis kanamycin susceptibility. GenoType MTBDRsl, a widely used assay evaluating this region, wrongly classified 17/410 isolates as eis-promoter wildtype. 6/17 isolates harbored mutations known to confer kanamycin resistance, and the remainder harbored either novel eis-promoter mutations (7/11) or disputed mutations (4/11). GenoType MTBDRsl can miss established and new variants that cause reduced susceptibility. These data highlight the importance of reflex phenotypic kanamycin testing.

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