12,302 research outputs found

    "Lesion journey" in hidradenitis suppurativa: clinical and ultrasonographic correlations

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    Introduzione: L'idrosadenite suppurativa (HS) √® una malattia immuno-mediata che colpisce i follicoli piliferi situati principalmente nelle aree ricche di ghiandole apocrine. Materiali e metodi: √ą stato condotto uno studio osservazionale prospettico monocentrico finalizzato a correlare i parametri clinici ed ecografici con: l'evoluzione delle lesioni, la probabilit√† di riacutizzazione o di andare incontro ad un trattamento chirurgico/laser-CO2. Risultati: Sono stati reclutati sessantuno pazienti con un'et√† media pari a 29,5 ¬Ī 7,5 anni che presentavano un numero basale di 127 noduli infiammatori, 43 ascessi e 62 fistole. Dopo un tempo medio di 77,9 settimane, rispettivamente il 40%, 14%, 8% di noduli, ascessi e fistole erano guariti, il 5%, 30%, 29% persistevano privi di infiammazione, il 47%, 33%, 63 % presentava uno stato infiammatorio, e l'8% e il 23% dei noduli e degli ascessi erano evoluti in fistole. Sono stati registrati 137 episodi di flare nelle lesioni acute (noduli + ascessi) e 54 nelle lesioni croniche (fistole), mentre il numero di interventi procedurali √® stato rispettivamente pari a 59 e 50. I fattori predittivi associati ad un'evoluzione sfavorevole (stato infiammatorio o cronicizzazione) per ascessi e noduli sono stati: evidenza ecografica di frammenti piliferi intralesionali, elevato segnale Power Doppler (PD) ed edema all'ecografia, profondit√† della localizzazione ed interessamento genitale; i predittori associati alle fistole sono stati: profondit√† della localizzazione, edema e dimensioni della lesione. La probabilit√† che una lesione acuta venisse sottoposta ad un intervento procedurale √® stata correlata a: et√†, presenza di frammenti piliferi, segnale PD, edema e profondit√† della localizzazione; per le fistole l'unico predittore indipendente √® stato la dimensione. I predittori di riacutizzazione della patologia per ascessi e noduli sono stati: giovane et√† all'esordio, segnale PD, evidenza ecografica di frammenti follicolari, profondit√† della localizzazione e dimensioni; per le fistole i predittori sono stati: localizzazione ascellare, profondit√† della localizzazione, edema e dimensione.Background: Hidradenitis suppurativa (HS) is an immune-mediated disorder affecting hair follicles mainly located in the apocrine gland-bearing area. It presents suppurative lesions consisting of nodules, abscesses, and fistulas that exhibit a variable degree of inflammatory activity. Materials and Methods: A prospective, single-center observational study was designed to correlate clinical and ultrasonographic parameters with the "lesions' evolution" at the end of the study, the probability of flaring or undergoing a surgical/CO2-laser intervention. Results: Sixty-one patients (25 males and 36 females) with a mean age of 29.5¬Ī7.5 years who had a total baseline number of 127 inflammatory nodules, 43 abscesses, and 62 fistulas were recruited. After a mean follow-up time of 77.9 weeks, 40%, 14%, 8% of nodules, abscesses, and fistulas respectively had healed, 5%, 30%, 29% were free of inflammation, 47%, 33%, 63% had an inflammatory status, and 8% and 23% of nodules and abscesses had evolved into fistulas. There were 137 flare episodes in the acute lesions (nodules + abscesses) and 54 in the chronic lesions (fistulas), while the number of procedural interventions was 59 and 50, respectively. The predictive factors associated with an unfavorable evolution (inflammatory status or chronicity) for abscesses and nodules were: presence of hair tracts, high degree of Power Doppler (PD) and edema on ultrasonography, depth of localization and genital body area; for fistulas the predictors were: depth of localization, edema, and size. The probability of an acute lesion going to procedural intervention correlated with: age, presence of hair tracts, high degree of PD, edema, and depth of localization; for fistulas the only independent predictor was size. The predictors of flare for abscesses and nodules were: young age at disease onset, PD signal, hair tracts, depth of localization, and size; in the case of fistulas the predictors were: axillary localization, depth of localization, edema, and size

    Studying the interplay between ageing and Parkinson's disease using the zebrafish model

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    Parkinson‚Äôs disease (PD) is a neurodegenerative disorder characterised by the loss of dopaminergic neurons in the substantia nigra. Ageing is the major risk factor for developing PD but the interplay between ageing and PD remains elusive. To investigate the effect of ageing on PD-relevant pathological mechanisms, zebrafish mutant lines harbouring mutations in ageing-associated genes (klotho-/-, sirt1-/-, satb1a-/-, satb1b-/- and satb1a-/-;satb1b-/-) were generated, using CRISPR/Cas9 gene editing. Likewise, a chemical model for SIRT1 deficiency was utilised. klotho-/- zebrafish displayed an accelerated ageing phenotype at 3mpf and reduced survival to 6mpf. Dopaminergic neuron number, MPP+ susceptibility and microglial number were unaffected in klotho-/- larvae. NAD+ levels were decreased in 6mpf klotho-/- brains. However, ATP levels and DNA damage were unaffected. sirt1-/- zebrafish did not display a phenotype through adulthood. il-1ő≤ and il-6 were not upregulated in sirt1-/- larvae, and chemical inhibition of sirt1 did not increase microglial number. cdkn1a, il-1ő≤ and il-6 were not upregulated in satb1a-/- and satb1b-/- larvae. Dopaminergic neuron number and MPP+ susceptibility were unaffected in satb1a-/- larvae. However, satb1b-/- larvae demonstrated a moderate decrease in dopaminergic neuron number but equal susceptibility to MPP+ as satb1b+/+ larvae. Adult satb1a-/- but not adult satb1b-/- zebrafish were emaciated. satb1a-/-;satb1b-/- zebrafish did not display a phenotype through adulthood. Transgenic zebrafish expressing human wildtype őĪ-Synuclein (Tg(eno2:hsa.SNCA-ires-EGFP)) were crossed with klotho-/- and sirt1-/- zebrafish, and treated with a sirt1-specific inhibitor. Neither genetic cross affected survival. The klotho mutation did not increase microglial number in Tg(eno2:hsa.SNCA-ires-EGFP) larvae. Likewise, sirt1 inhibition did not induce motor impairment or cell death in Tg(eno2:hsa.SNCA-ires-EGFP) larvae. In conclusion, the suitability of zebrafish for studying ageing remains elusive, as only 1 ageing-associated mutant line displayed accelerated ageing. However, zebrafish remain an effective model for studying PD-relevant pathological mechanisms due to the availability of CRISPR/Cas9 gene editing, neuropathological and neurobehavioral tools

    Ethyl gallate isolated from phenol-enriched fraction of Caesalpinia mimosoides Lam. Promotes cutaneous wound healing: a scientific validation through bioassay-guided fractionation

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    The tender shoots of Caesalpinia mimosoides Lam. are used ethnomedically by the traditional healers of Uttara Kannada district, Karnataka (India) for the treatment of wounds. The current study was aimed at exploring phenol-enriched fraction (PEF) of crude ethanol extract of tender shoots to isolate and characterize the most active bio-constituent through bioassay-guided fractionation procedure. The successive fractionation and sub-fractionation of PEF, followed by in vitro scratch wound, antimicrobial, and antioxidant activities, yielded a highly active natural antioxidant compound ethyl gallate (EG). In vitro wound healing potentiality of EG was evidenced by a significantly higher percentage of cell migration in L929 fibroblast cells (97.98 ¬Ī 0.46% at 3.81¬†őľg/ml concentration) compared to a positive control group (98.44 ¬Ī 0.36%) at the 48th hour of incubation. A significantly higher rate of wound contraction (98.72 ¬Ī 0.41%), an elevated tensile strength of the incised wound (1,154.60 ¬Ī 1.42¬†g/mm2), and increased quantity of connective tissue elements were observed in the granulation tissues of the 1% EG ointment treated animal group on the 15th post-wounding day. The accelerated wound healing activity of 1% EG was also exhibited by histopathological examinations through Hematoxylin and Eosin, Masson‚Äôs trichome, and Toluidine blue-stained sections. Significant up-regulation of enzymatic and non-enzymatic antioxidant contents (reduced glutathione, superoxide dismutase, and catalase) and down-regulation of oxidative stress marker (lipid peroxidation) clearly indicates the effective granular antioxidant activity of 1% EG in preventing oxidative damage to the skin tissues. Further, in vitro antimicrobial and antioxidant activities of EG supports the positive correlation with its enhanced wound-healing activity. Moreover, molecular docking and dynamics for 100¬†ns revealed the stable binding of EG with cyclooxygenase-2 (‚ąí6.2¬†kcal/mol) and matrix metalloproteinase-9 (‚ąí4.6¬†kcal/mol) and unstable binding with tumor necrosis factor-őĪ (‚ąí7.2¬†kcal/mol), suggesting the potential applicability of EG in inflammation and wound treatment

    Homeostasis in Immunity-Related Pupal Tissues of the Malaria Mosquito Anopheles gambiae and its regulation by the NF-kappaB-like Factor Rel2

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    Die Haut ist eine oft √ľbersehene Komponente des angeborenen Immunsystems der M√ľcken. Die Haut der M√ľcke bildet eine physische Barriere, die die mikrobielle Hom√∂ostase aufrechterh√§lt, das Eindringen von Toxinen wie Insektiziden verhindert und das Austrocknen verhindert. Die am meisten untersuchten Akteure des Immunsystems von Stechm√ľcken sind das Fettgewebe und die Blutzellen, aber die Hauttalg-Fabriken, die Oenozyten, werden in Studien nur selten ber√ľcksichtigt. M√ľckenpuppen haben aktiv funktionierende immunit√§tsbezogene Organe, einschlie√ülich derjenigen, die Hautbarrieren produzieren. Ihre biologische Rolle in diesem Entwicklungsstadium ist kaum bekannt, aber der √úbergang von der Puppen- zur Erwachsenenhaut und die Auff√§lligkeit der talgproduzierenden Zellen machen dieses Stadium zu einem vielversprechenden Entwicklungsstadium f√ľr die Untersuchung der Hautbildung. Mit Hilfe der Transkriptomanalyse beschreiben wir die Rolle der Blutzellen bei der Entwicklung des chitin√∂sen Teils der Insektenhaut, die Beteiligung des Fettk√∂rpers an der Immunit√§t und best√§tigen die Rolle der talgproduzierenden Zellen im Lipidstoffwechsel. Dar√ľber hinaus beschreiben wir talgsezernierende Zellen als einen bedeutenden Wirkungsort des NF-kappaB-√§hnlichen IMD-Rel2-Pathway, in dem der Transkriptionsfaktor Rel2 die Retinoid-Hom√∂ostase reguliert. Schlie√ülich best√§tigen wir eine 100 Jahre alte Beobachtung, wonach sebumsezernierende Zellen der Stechm√ľcke ihren Zellinhalt in einem Netzwerk von Vesikeln absondern. Wir beschreiben extrazellul√§res Chromatin als Fracht in diesem Vesikelnetzwerk und sein antimikrobielles Potenzial.The skin is an often overlooked component of the mosquito's innate immune system. The mosquito skin provides a physical barrier that maintains microbial homeostasis, prevents the entry of toxins like insecticides, and avoids desiccation. The most studied players in the immune system of mosquitoes are the adipose tissue and blood cells, but studies rarely consider the skin sebum factories, oenocytes. Mosquito pupae have actively functional immunity-related organs, including those producing skin barriers. Their biological roles at this developmental stage are poorly understood, but the pupae-to-adult metamorphic skin transition and the conspicuity of sebum-secreting cells make it a promising developmental stage to study skin formation. We use transcriptomics to describe the role of blood cells in the development of the chitinous section of the insect skin, the involvement of the fat body in immunity, and confirm the lipid metabolism role of sebum-secreting cells. Furthermore, we describe sebum-secreting cells as a significant action site of the NF-kappaB-like IMD-Rel2 pathway where the transcription factor Rel2 regulates retinoid homeostasis. Finally, we confirm a 100-year-old observation of how mosquito sebum-secreting cells secrete their cellular contents in a network of vesicles. We describe extracellular chromatin as cargo inside this vesicle network and its antimicrobial potential

    Living Labor

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    For much of the twentieth century, the iconic figure of the U.S. working class was a white, male industrial worker. But in the contemporary age of capitalist globalization new stories about work and workers are emerging to refashion this image. Living Labor examines these narratives and, in the process, offers an innovative reading of American fiction and film through the lens of precarious work. It argues that since the 1980s, novelists and filmmakers‚ÄĒincluding Russell Banks, Helena V√≠ramontes, Karen Tei Yamashita, Francisco Goldman, David Riker, Ramin Bahrani, Clint Eastwood, Courtney Hunt, and Ryan Coogler‚ÄĒhave chronicled the demise of the industrial proletariat, and the tentative and unfinished emergence of a new, much more diverse and perilously positioned working class. In bringing together stories of work that are also stories of race, ethnicity, gender, and colonialism, Living Labor challenges the often-assumed division between class and identity politics. Through the concept of living labor and its discussion of solidarity, the book reframes traditional notions of class, helping us understand both the challenges working people face and the possibilities for collective consciousness and action in the global present

    Healing Grief: A Commentary on Seneca's Consolatio ad Marciam

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    Both our view of Seneca‚Äôs philosophical thought and our approach to the ancient consolatory genre have radically changed since the latest commentary on the Consolatio ad Marciam was written in 1981. The aim of this work is to offer a new book-length commentary on the earliest of Seneca‚Äôs extant writings, along with a revision of the Latin text and a reassessment of Seneca‚Äôs intellectual program, strategies, and context. A crucial document to penetrate Seneca‚Äôs discourse on the self in its embryonic stages, the Ad Marciam is here taken seriously as an engaging attempt to direct the persuasive power of literary models and rhetorical devices toward the fundamentally moral project of healing Marcia‚Äôs grief and correcting her cognitive distortions. Through close reading of the Latin text, this commentary shows that Seneca invariably adapts different traditions and voices ‚Äď from Greek consolations to Plato‚Äôs dialogues, from the Roman discourse of gender and exemplarity to epic poetry ‚Äď to a Stoic framework, so as to give his reader a lucid understanding of the limits of the self and the ineluctability of natural laws

    Emerging radiopharmaceuticals for PET-imaging gliomas. A multi-: radiopharmaceutical, camera, modality, model, and modelling assessment

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    Gliomas, which are a type of brain tumour derived from the non-neuronal and nutrient-supplying glial cells of the brain, are particularly devastating disease due to the importance and delicate nature of cerebral matter. Surgical removal, chemotherapy, and radiation therapy often have unwanted consequences depending on a variety of physiological and probability factors. With the human life expectancy averaging 12-15 months after clinical diagnosis (with treatment) for aggressive brain tumours, accurately detecting and characterizing these tumours non-invasively is important for treatment planning. Currently, the highest anatomical resolution imaging modality available for brain imaging is magnetic resonance imaging (MRI), but this lacks biochemical information. Positron emission tomography paired with computed tomography for anatomical reference (PET-CT) divulges quantifiable biochemical information. By selecting imaging radiopharmaceuticals for PET imaging that have relevance to tumour surface proteins or other cellular metabolic processes it is possible to not only aid in detecting or delineating gliomas, but also gain specific biochemical-property insight into these lesions. The aim of these studies was to evaluate the two emerging radiopharmaceuticals (2S, 4R)-4-[18F]fluoroglutamine ([18F]FGln) and Al[18F]F-NOTA-Folate ([18F]FOL) and to directly compare them with routinely clinically-used radiopharmaceuticals 2-deoxy-2-[18F]fluoro-ŠīÖ-glucose ([18F]FDG) and  ü-[11C]methionine ([11C]Met) for the PET imaging of gliomas in animal models. Other parameters, such as the in vivo stability, ex vivo biodistribution, in vitro binding and blocking, and the presence of relevant receptors on human tissue samples were investigated in to divulge additional information. The results demonstrated that both [18F]FGln and [18F]FOL provided an enhanced level of contrast between tumour and adjacent non-tumour brain tissue versus that of the clinically used radiopharmaceuticals [18F]FDG and [11C]Met in animal models.Uudet radiol√§√§keaineet glioomien PET-kuvantamiseen. Tutkimuksia radiol√§√§keaineista, modaliteeteista, kameroista, kokeellisista malleista ja mallintamisesta Glioomat ovat aivokasvaimia, jotka syntyv√§t ravinteiden kuljetusta hoitavista glia- eli hermotukisoluista. Ne ovat erityisen tuhoisia sairauksia aivokudoksen t√§rkeyden ja herkkyyden vuoksi. Kirurgisella leikkauksella, kemoterapialla, ja s√§dehoidolla on usein ei-toivottuja seurauksia riippuen fysiologisista ja todenn√§k√∂isyystekij√∂ist√§. Koska elinajanodote aggressiivisen aivokasvaimen diagnoosin j√§lkeen on keskim√§√§rin 12‚Äď15 kuukautta (hoidon kanssa), ei-invasiivinen tarkka havaitseminen ja karakterisointi on t√§rke√§√§ hoidon suunnittelussa. T√§ll√§ hetkell√§ parhaat ty√∂kalut aivojen kuvantamiseen ovat magneettikuvaus (MRI), joka mahdollistaa parhaimman anatomisen tarkkuuden, ja positroniemissiotomografia (PET), joka paljastaa biokemiallisen informaation. Valitsemalle PET-kuvantamiseen radiol√§√§keaine, joka kiinnittyy sy√∂p√§solun pintaproteiineihin tai liittyy solun aineenvaihduntaprosessiin on mahdollista paitsi havaita tai rajata glioomia, my√∂s saada erityist√§ biokemiallista tietoa n√§ist√§ leesioista. T√§m√§n tutkimuksen tavoitteena oli arvioida kahta uutta radiol√§√§keainetta; (2S, 4R)-4-[18F]fluoriglutamiinia ([18F]FGln) ja Al[18F]F-NOTA-folaattia ([18F]FOL) ja verrata niit√§ kliinisess√§ k√§yt√∂ss√§ oleviin 2-deoxy-2-[18F]fluori-ŠīÖ-glukoosiin ([18F]FDG) ja  ü-[11C]metioniiniin ([11C]Met) glioomien PET-kuvantamisessa. Stabiilisuutta, biologista jakautumista, sitoutumista ja sitoutumisen salpautumista, sek√§ farmakokineettista mallintamista tutkittiin in vivo, ex vivo ja in vitro olosuhteissa el√§inmalleissa ja kudosn√§ytteill√§. Tulokset osoittivat, ett√§ el√§inmalleissa sek√§ [18F]FGln ett√§ [18F]FOL mahdollistavat paremman kontrastin tuumorin ja viereisen tuumorittoman aivokudoksen v√§lill√§ verrattuna kliinisess√§ k√§yt√∂ss√§ oleviin [18F]FDG ja [11C]Met radiol√§√§keaineisiin

    Targeting lymphoid-derived IL-17 signaling to delay skin aging

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    Skin aging is characterized by structural and functional changes that contribute to age-associated frailty. This probably depends on synergy between alterations in the local niche and stem cell-intrinsic changes, underscored by proinflammatory microenvironments that drive pleotropic changes. The nature of these age-associated inflammatory cues, or how they affect tissue aging, is unknown. Based on single-cell RNA sequencing of the dermal compartment of mouse skin, we show a skew towards an IL-17-expressing phenotype of T helper cells, ő≥őī‚ÄČT cells and innate lymphoid cells in aged skin. Importantly, in vivo blockade of IL-17 signaling during aging reduces the proinflammatory state of the skin, delaying the appearance of age-related traits. Mechanistically, aberrant IL-17 signals through NF-őļB in epidermal cells to impair homeostatic functions while promoting an inflammatory state. Our results indicate that aged skin shows signs of chronic inflammation and that increased IL-17 signaling could be targeted to prevent age-associated skin ailments.¬© 2023. The Author(s)

    Dissecting the effect of EGF starvation on the signaling and transcriptomic landscapes of the mouse intestinal epithelium

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    Die EGFR-Signal√ľbertragung steuert viele verschiedene zellul√§re Prozesse in allen Arten von Epithelzellen, einschlie√ülich des Darmepithels. Diese Prozesse reichen von Proliferation und Wachstum √ľber Differenzierung bis hin zu Autophagie und Apoptose. Die vorliegende Studie zielt darauf ab, die Signalver√§nderungen zu charakterisieren, die im Darmepithel als Reaktion auf EGF-induzierten Hungerstress stattfinden. Kontraintuitiv f√ľhrte eine 24-st√ľndige EGF-Starre zu einer deutlichen Phosphorylierung von EGFR, MEK1/2 und ERK1/2, was auf eine Aktivierung dieser Signalachse in Darmzellen hindeutet. Diese Ver√§nderungen waren am signifikantesten in den undifferenzierten CD44-reichen Krypta-Basiszellen. Interessanterweise war die EGF-Starvation-induzierte ERK1/2-Phosphorylierung mit der Hochregulierung einer Untergruppe von ERK-Zielgenen verbunden, bei denen es sich zumeist um prim√§re Zielgene handelt. Die √úberexpression des EGFR-Liganden HBEGF und des FGFR-Liganden FGF1 in ausgehungerten Zellen k√∂nnte f√ľr die hungerbedingte Zunahme der MAPK-Aktivit√§t verantwortlich sein, obwohl eine erh√∂hte Sekretion dieser Liganden durch ausgehungerte Organoide nicht best√§tigt werden konnte. Dennoch wird die kompensatorische Ligandensekretion durch die Beobachtung gest√ľtzt, dass die erneute Zugabe von EGF zu ausgehungerten Organoiden die pERK1/2-Spiegel auf den Ausgangswert zur√ľcksetzt, was bedeutet, dass EGF mit einem anderen von ausgehungerten Zellen sezernierten Liganden um den EGFR konkurriert. Zus√§tzlich zu HBEGF wurde festgestellt, dass andere Gene, die f√ľr den Schutz, das √úberleben und die Regeneration des Darmepithels bekannt sind, in ausgehungerten Organoiden √ľberexprimiert werden, wie z. B. Reg3b. Insgesamt k√∂nnen die in dieser Studie berichteten EGF-induzierten Ver√§nderungen der MAPK-Signal√ľbertragung und der globalen Genexpression als ein √ľberlebensf√∂rderndes Programm interpretiert werden, das bevorzugt in Darmstammzellen und fr√ľhen Vorl√§uferzellen aktiviert wird.EGFR signaling drives many different cellular processes in all kinds of epithelial cells including the intestinal epithelium. Such processes range from proliferation and growth to differentiation to autophagy and apoptosis. The present study aims to characterize signaling changes that take place in the intestinal epithelium in response to EGF starvation-induced stress using epithelial organoids derived from the mouse duodenum and human colorectal tumor tissue. Counterintuitively, 24 h EGF starvation induced a prominent phosphorylation of EGFR, MEK1/2 and ERK1/2 indicating an activation of this signaling axis in intestinal cells. These changes were most significant in the undifferentiated CD44-high crypt base cells. Interestingly, EGF starvation-induced ERK1/2 phosphorylation was associated with upregulation of a subset of ERK target genes that were mostly primary-response targets. Overexpression of the EGFR ligand HBEGF and the FGFR ligand FGF1 in starved cells may account for starvation-driven increase in MAPK activity, although an increased secretion of these ligands by starved organoids was not confirmed. Nevertheless, compensatory ligand secretion is still supported by the observation that EGF re-addition to starved organoids restores pERK1/2 levels to baseline which implies that EGF competes for EGFR with some other ligand secreted by starved cells. In addition to HBEGF, other genes known to promote protection, survival and regeneration of the intestinal epithelium were found to be overexpressed in starved organoids such as Reg3b. Collectively, EGF starvation-induced changes in MAPK signaling and global gene expression reported in this study can be interpreted as a pro-survival program that gets activated preferentially in intestinal stem cells and early progenitors
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