Genital warts: comparing clinical findings to dermatoscopic aspects, in vivo reflectance confocal features and histopathologic exam

Интеграция метаболизма макроорганизма и его микробиоты, обеспечивающая в норме симбиоз и саногенез, нарушается при заболеваниях, травме, критическом состоянии, и вектор взаимодействия может изменяться в пользу прокариотов по принципу «метаболиты бактерий - против хозяина». Анализ литературы показал, что, с одной стороны, имеется живой интерес к ароматическим микробным метаболитам, с другой - отсутствует четкое представление об их роли в организме человека. Публикации, касающиеся ряда ароматических микробных метаболитов (фенилкарбоновых кислот, ФКК), как правило, не связаны между собой по тематике и направлены на решение тех или иных прикладных задач в разных областях биологии и медицины. Цель обзора - анализ информации о происхождении, биологических эффектах ФКК в экспериментах in vitro и in vivo , и клинических наблюдениях. Обобщая результаты приведенных в обзоре исследований на клеточном, субклеточном и молекулярном уровнях, логично предположить участие ароматических микробных метаболитов в патогенезе полиорганной недостаточности при сепсисе. Наиболее перспективным для раскрытия роли ароматических микробных метаболитов представляется изучение механизмов вторичной почечной недостаточности и септической энцефалопатии. Важным направлением для будущих исследований является изучение влияния продуктов микробной биодеградации ароматических соединений на развитие диссеминированного внутрисосудистого свертывания крови, артериальной гипотензии и септического шока. Результаты дальнейших исследований будут иметь не только фундаментальное значение, но и обогатят практическую медицину новыми диагностическими и лечебными технологиями. Significant increases in blood concentrations of some aromatic metabolites (phenylcarboxylic acids, PhCAs) in patients with sepsis have been previously shown. Enhanced bacterial biodegradation of aromatic compounds has been demonstrated to considerably contribute to this process. Integration of macroorganism metabolism and its microbiota, which provides normal symbiosis and sanogenesis, is disturbed in diseases, trauma, and critical conditions. Direction of this interaction may change in favor of prokaryotes according to the principle, “bacterial metabolites are against the host”. Analysis of literature showed a particular interest of many investigators to aromatic microbial metabolites. However, there is no clear understanding of their role in the human body. Publications on PhCAs are generally not thematically interrelated and usually focus on solving applied tasks in different fields of biology and medicine. The aim of this work was to consolidate existing information about origin and biological effects of PhCAs in in vitro / in vivo experiments and some clinical findings. The presented summary of reported data from studies performed at cellular, sub-cellular, and molecular levels suggests participation of aromatic microbial metabolites in the pathogenesis of multiple organ failure in sepsis. Studying mechanisms of secondary renal failure and septic encephalopathy is most promising for discovering the function of aromatic microbial metabolites. Effects of microbial biodegradation products of aromatic substances on development of disseminated intravascular coagulation, hypotension, and septic shock are an important challenge for future studies. Results of further investigations will be not only fundamental, but will also enrich medical practice with new diagnostic and therapeutic technologies.

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Neurochemical and Pharmacological Properties of Tianeptine, A Novel Antidepressant

The British Journal of Psychiatry ◽

10.1192/s0007125000296694 ◽

1992 ◽

Vol 160 (S15) ◽

pp. 56-60 ◽

Cited By ~ 25

Author(s):

C. Labrid ◽

E. Mocaër ◽

A. Kamoun

Keyword(s):

Rat Brain ◽

Ex Vivo ◽

Animal Experiments ◽

Pyramidal Cells ◽

Human Platelets ◽

Clinical Findings ◽

Tricyclic Antidepressant ◽

Laboratory Animals ◽

5 Ht Uptake

Tianeptine is a tricyclic antidepressant with an unusual chemical structure (a long lateral chain grafted on to a substituted dibenzothiazepin nucleus), and with biochemical and animal-behavioural properties which are strikingly different from those of classical tricyclics. Unlike the latter, which decrease serotonin (5-HT) uptake, acute and chronic tianeptine treatment enhances 5-HT uptake in rat brain and in rat and human platelets ex vivo. In vivo, tianeptine potentiates the depletion of rat brain 5-HT by 4-methyl-alpha-ethyl metatyramine and increases rat hippocampal 5-HIAA; 5-HT uptake inhibitors (e.g. fluoxetine) have opposite effects. On iontophoretic injection into CA1 pyramidal cells, tianeptine shortens the period of neuronal hypoactivity caused by GABA or 5-HT, whereas other tricyclics prolong it, and it enhances attention, learning, and memory in laboratory animals, while classical tricyclics have opposite effects. However, the relationships between these effects of tianeptine in animal experiments and their relevance to clinical findings remain to be determined.

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Development of a Physiologically Based Pharmacokinetic Model for Hydroxychloroquine and Its Application in Dose Optimization in Specific COVID-19 Patients

Frontiers in Pharmacology ◽

10.3389/fphar.2020.585021 ◽

2021 ◽

Vol 11 ◽

Author(s):

Miao Zhang ◽

Xueting Yao ◽

Zhe Hou ◽

Xuan Guo ◽

Siqi Tu ◽

...

Keyword(s):

Pbpk Model ◽

Clinical Findings ◽

Lung Model ◽

Elderly Subjects ◽

Distribution Data ◽

Physiologically Based Pharmacokinetic ◽

Physiologically Based ◽

Drug Actions

In Feb 2020, we developed a physiologically-based pharmacokinetic (PBPK) model of hydroxychloroquine (HCQ) and integrated in vitro anti-viral effect to support dosing design of HCQ in the treatment of COVID-19 patients in China. This, along with emerging research and clinical findings, supported broader uptake of HCQ as a potential treatment for COVID-19 globally at the beginning of the pandemics. Therefore, many COVID-19 patients have been or will be exposed to HCQ, including specific populations with underlying intrinsic and/or extrinsic characteristics that may affect the disposition and drug actions of HCQ. It is critical to update our PBPK model of HCQ with adequate drug absorption and disposition mechanisms to support optimal dosing of HCQ in these specific populations. We conducted relevant in vitro and in vivo experiments to support HCQ PBPK model update. Different aspects of this model are validated using PK study from 11 published references. With parameterization informed by results from monkeys, a permeability-limited lung model is employed to describe HCQ distribution in the lung tissues. The updated model is applied to optimize HCQ dosing regimens for specific populations, including those taking concomitant medications. In order to meet predefined HCQ exposure target, HCQ dose may need to be reduced in young children, elderly subjects with organ impairment and/or coadministration with a strong CYP2C8/CYP2D6/CYP3A4 inhibitor, and be increased in pregnant women. The updated HCQ PBPK model informed by new metabolism and distribution data can be used to effectively support dosing recommendations for clinical trials in specific COVID-19 patients and treatment of patients with malaria or autoimmune diseases.

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Normal Development and Malformations of the Cerebellar Cortex

Rivista di Neuroradiologia ◽

10.1177/197140090301600310 ◽

2003 ◽

Vol 16 (3) ◽

pp. 383-391

Author(s):

B. Bernardi ◽

F. Roncaroli

Keyword(s):

Cerebellar Cortex ◽

Normal Development ◽

Current Knowledge ◽

Clinical Findings ◽

Cellular Organization ◽

Developmental Abnormalities ◽

Cerebellar Malformations ◽

The Central Nervous System

The cerebellum is one of the first structures of the central nervous system that begins differentiation and one of the last to reach maturity. Neurogenesis of granular neurons is largely postnatal and cellular organization continues several months after birth. This protracted maturation causes susceptibility to developmental abnormalities. Such abnormalities encompass structural malformations and even cerebellar tumors. Current knowledge on the development of the cerebellar cortex is increasing. Cerebellar cortex development includes proliferation, migration, neuronal differentiation, guided axonal growth, neuronal map formation and synaptogenesis. These steps follow different timing and modalities compared to neocortex. The high resolution Magnetic Resonance (MR) improved the in vivo depiction of the cerebellar cortex and its developmental malformations. Correlation between neuroimaging and clinical findings as well as neurogenetic allowed practical classification of cerebellar malformations. The proposed morphology-based classifications appear incomplete and need continuous revision. In this review, we have followed a neuroradiological schema in order to reconcile previous classifications. Sviluppo normale e malformazioni della corteccia cerebellare

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Atypical Bilateral Fuchs Uveitis: Diagnostic Challenges

Case Reports in Ophthalmology ◽

10.1159/000439081 ◽

2015 ◽

Vol 6 (3) ◽

pp. 284-288 ◽

Cited By ~ 1

Author(s):

Cristóbal Couto ◽

Erika Hurtado ◽

Dana Faingold ◽

Carmen Demetrio ◽

Ariel Schlaen ◽

...

Keyword(s):

Case Report ◽

Laboratory Tests ◽

Clinical Findings ◽

Posterior Segment ◽

In Vivo Confocal Microscopy ◽

Keratic Precipitates ◽

Vitreous Opacities ◽

High Index Of Suspicion ◽

Rule Out

Bilateral Fuchs uveitis associated with vitreous infiltration and posterior segment involvement requires a thorough diagnostic evaluation. The lack of well-defined diagnostic criteria makes identification of this entity difficult. The aim of this case report was to present the characteristics of a patient with atypical Fuchs uveitis and the procedures needed to rule out the differential diagnosis with specific attention to the utility of in vivo confocal microscopy (IVCM). Case Report: One case of chronic bilateral uveitis with severe vitreous opacities is presented. After extensive systemic workup, including vitrectomy, the case had no identifiable systemic etiology. IVCM of the cornea revealed the presence of dendritiform keratic precipitates. Conclusion: The diagnosis of Fuchs uveitis is based on clinical findings as no confirmatory laboratory tests are available. A high index of suspicion is key to an early diagnosis, especially in the cases with vitreous opacities and posterior segment manifestations. Auxiliary tests such as IVCM may aid the clinician in the diagnosis of Fuchs uveitis.

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Osteoblast cell signalling: have our views have changed?

Faculty Dental Journal ◽

10.1308/204268512x13226622491868 ◽

2012 ◽

Vol 3 (1) ◽

pp. 56-61

Author(s):

Fraser McDonald

Keyword(s):

Tooth Movement ◽

Care Delivery ◽

Cell Signalling ◽

Orthodontic Tooth Movement ◽

Cellular Level ◽

Clinical Findings ◽

External Loading ◽

Relative Role ◽

Tissue Fluid

Many theories are advanced with respect to the behaviour of bone under external loading. Essentially they divide into external loading (with respect to tension and compression), tissue-fluid-based theories and electrical-based theories. While this appears to be a distinct classification with regard to an understanding of these theories, it must be emphasised that each theory has a significant inter-relationship with the others. It is also essential to differentiate that, while an effect can be identified at the cellular level, the relative importance and significance of this can be limited in vivo and its relative role and importance overwhelmed by other loading issues. In this article consideration is given to a possible basis of orthodontic tooth movement and like so many other hypotheses it is difficult to directly evaluate and measure; it must be considered by deduction of current known facts. The concept was initially reported when comparing bone remodelling in a femur with orthodontic tooth movement;1 further data is now available although the concept is not completely acceptable. It does, however, produce an explanation for some clinical findings which assist us in our orthodontic care delivery.

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Hope in the Treatment of Candida Vaginitis: Ibrexafungerp

Türk Mikrobiyoloji Cemiyeti Dergisi ◽

10.5222/tmcd.2021.71602 ◽

2021 ◽

Author(s):

Ayşe Sultan Karakoyun

Keyword(s):

Current Knowledge ◽

Public Health Problem ◽

Clinical Findings ◽

Antifungal Drugs ◽

Drug Resistant ◽

Over The Counter ◽

Synthase Inhibitor ◽

Increased Activity

Candida vaginitis (CV) is a neglected but growing public health problem. It is estimated that three out of four women have had at least one CV attack. The diagnosis and treatment of CV is often inadequate due to the tendency of women to self-diagnose and use over-the-counter drugs when they have vaginal or vulvar complaints, and clinicians plan treatment only according to clinical findings. There are limitations regarding the safety and efficacy of oral azoles, which are primarily preferred for the treatment of vaginitis, and these drugs have not revealed the desired levels of clinical or mycological cure. Also, there are a few options for current drugs used for treatment are not numerous the development of new antifungal drugs is thus urgently needed. Ibrexafungerp (IBX) is a semisynthetic triterpenoid glucan synthase inhibitor derived from enfumafungin. IBX has been shown to be a promising oral antifungal in the treatment of acute CV, and its use was approved on June 1, 2021. IBX is remarkable by it’s high oral bioavailability, low risk of side effects, few drug-drug interactions, good tissue penetration, increased activity at low pH in the vagina, and efficacy with regard to multi-drug-resistant fungi. In this review, in vitro and in vivo data on IBX were evaluated and compiled in light of current knowledge.

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Lovastatin lactone may improve irritable bowel syndrome with constipation (IBS-C) by inhibiting enzymes in the archaeal methanogenesis pathway

F1000Research ◽

10.12688/f1000research.8406.1 ◽

2016 ◽

Vol 5 ◽

pp. 606 ◽

Cited By ~ 1

Author(s):

Steven M. Muskal ◽

Joe Sliman ◽

John Kokai-Kun ◽

Mark Pimentel ◽

Vince Wacher ◽

...

Keyword(s):

Irritable Bowel Syndrome ◽

Structural Information ◽

Methanogenic Archaea ◽

Clinical Findings ◽

Ligand Docking ◽

Cholesterol Lowering ◽

Lactone Form ◽

Natural Ligand ◽

Irritable Bowel

Methane produced by the methanoarchaeonMethanobrevibacter smithii(M. smithii) has been linked to constipation, irritable bowel syndrome with constipation (IBS-C), and obesity. Lovastatin, which demonstrates a cholesterol-lowering effect by the inhibition of HMG-CoA reductase, may also have an anti-methanogenesis effect through direct inhibition of enzymes in the archaeal methanogenesis pathway. We conducted protein-ligand docking experiments to evaluate this possibility. Results are consistent with recent clinical findings.METHODS: F420-dependent methylenetetrahydromethanopterin dehydrogenase (mtd), a key methanogenesis enzyme with a known sequence but no tertiary protein structural information, was modeled for two different methanogenic archaea:M. smithiiandMethanopyrus kandleri. Once protein models were developed, ligand-binding sites were identified. Multiple ligands and their respective protonation, isomeric and tautomeric representations were docked into each site, including F420-coenzyme (natural ligand), lactone and β-hydroxyacid forms of lovastatin and simvastatin, and other co-complexed ligands found in related crystal structures.RESULTS: 1) Generally, for each modeled site the lactone form of the statins had more favorable site interactions compared to F420; 2) The statin lactone forms generally had the most favorable docking scores, even relative to the native template PDB ligands; and 3) The statin β-hydroxyacid forms had less favorable docking scores, typically scoring in the middle with some of the F420 tautomeric forms. Consistent with these computational results were those from a recent phase II clinical trial (NCT02495623) with a proprietary, modified-release lovastatin-lactone (SYN-010) in patients with IBS-C, which showed a reduction in symptoms and breath methane levels, compared to placebo.CONCLUSION: The lactone form of lovastatin exhibits preferential binding over the native-F420 coenzyme ligandin silicoand thus could inhibit the activity of the keyM. smithiimethanogenesis enzymemtdin vivo. Statin lactones may thus exert a methane-reducing effect that is distinct from cholesterol lowering activity, which requires HMGR inhibition by statin β-hydroxyacid forms.

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Update on the Molecular Genetics of Timothy Syndrome

Frontiers in Pediatrics ◽

10.3389/fped.2021.668546 ◽

2021 ◽

Vol 9 ◽

Author(s):

Rosemary Bauer ◽

Katherine W. Timothy ◽

Andy Golden

Keyword(s):

Case Reports ◽

Clinical Findings ◽

Future Research ◽

Timothy Syndrome ◽

Genetic Changes ◽

Neurodevelopmental Delay ◽

Future Research Directions ◽

Prolonged Qt Interval ◽

Biophysical Changes

Timothy Syndrome (TS) (OMIM #601005) is a rare autosomal dominant syndrome caused by variants in CACNA1C, which encodes the α1C subunit of the voltage-gated calcium channel Cav1.2. TS is classically caused by only a few different genetic changes and characterized by prolonged QT interval, syndactyly, and neurodevelopmental delay; however, the number of identified TS-causing variants is growing, and the resulting symptom profiles are incredibly complex and variable. Here, we aim to review the genetic and clinical findings of all published case reports of TS to date. We discuss multiple possible mechanisms for the variability seen in clinical features across these cases, including mosaicism, genetic background, isoform complexity of CACNA1C and differential expression of transcripts, and biophysical changes in mutant CACNA1C channels. Finally, we propose future research directions such as variant validation, in vivo modeling, and natural history characterization.

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Radiation Medical Countermeasures and Use of EPR Biodosimetry to Facilitate Effectiveness of Applied Clinical Procedures

Applied Magnetic Resonance ◽

10.1007/s00723-021-01444-w ◽

2021 ◽

Author(s):

Vijay K. Singh ◽

Harold M. Swartz ◽

Thomas M. Seed

Keyword(s):

Radiation Dose ◽

Ionizing Radiation ◽

Radiation Exposure ◽

Medical Management ◽

Clinical Findings ◽

In Vivo Dosimetry ◽

Clinical Procedures ◽

Clinically Significant ◽

Medical Countermeasures

AbstractThe utility for electron paramagentic resonance (EPR or ESR)-based radiation biodosimetry has received increasing recognition concerning its potential to assist in guiding the clinical management of medical countermeasures in individuals unwantedly exposed to injurious levels of ionizing radiation. Similar to any of the standard physical dosimetric methods currently employed for screening clinically significant radiation exposures, the EPR-based in vivo dosimetry approach would serve to complement and extend clinical assessments (e.g., blood analyses, cytogenetics, etc.), specifically to more accurately assign the extent of ionizing radiation exposure that individuals might have received. In the case of EPR biodosimetry of biological samples such as nails, teeth, and bones, the method has the capability of providing information on the physical dose at several specific bodily sites and perhaps additonal information on the homogeneity of the exposure as well as its overall magnitude. This information on radiation dose and distribution would be of significant value in providing medical management to given individuals at health risk due to radiation exposure. As these measurements provide information solely on physical measures of the radiation dose and not on the potential biological impact of a particular dose, they are complementary, albeit supplemental, to the array of currently available biologically based biodosimetry and clinical findings. In aggregate, these physical and biological measures of radiation exposure levels (dose) would most certainly provide additional, useful information for the effective medical management of radiation exposed individuals.

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