Human keratinocytes are vanilloid resistant

BACKGROUND: Use of capsaicin or resiniferatoxin (RTX) as analgesics is an attractive therapeutic option. RTX opens the cation channel inflammatory pain/vanilloid receptor type 1 (TRPV1) permanently and selectively removes nociceptive neurons by Ca(2+)-cytotoxicity. Paradoxically, not only nociceptors, but non-neuronal cells, including keratinocytes express full length TRPV1 mRNA, while patient dogs and experimental animals that underwent topical treatment or anatomically targeted molecular surgery have shown neither obvious behavioral, nor pathological side effects. METHODS: To address this paradox, we assessed the vanilloid sensitivity of the HaCaT human keratinocyte cell line and primary keratinocytes from skin biopsies. RESULTS: Although both cell types express TRPV1 mRNA, neither responded to vanilloids with Ca(2+)-cytotoxicity. Only ectopic overproduction of TRPV1 rendered HaCaT cells sensitive to low doses (1-50 nM) of vanilloids. The TRPV1-mediated and non-receptor specific Ca(2+)-cytotoxicity ([RTX]>15 microM) could clearly be distinguished, thus keratinocytes were indeed resistant to vanilloid-induced, TRPV1-mediated Ca(2+)-entry. Having a wider therapeutic window than capsaicin, RTX was effective in subnanomolar range, but even micromolar concentrations could not kill human keratinocytes. Keratinocytes showed orders of magnitudes lower TRPV1 mRNA level than sensory ganglions, the bona fide therapeutic targets in human pain management. In addition to TRPV1, TRPV1b, a dominant negative splice variant was also noted in keratinocytes. CONCLUSION: TRPV1B expression, together with low TRPV1 expression, may explain the vanilloid paradox: even genuinely TRPV1 mRNA positive cells can be spared with therapeutic (up to micromolar) doses of RTX. This additional safety information might be useful for planning future human clinical trials

Canine pemphigus folliaceus: report of five clinical case

Η φυλλώδης πέμφιγα (ΦΠ), που αποτελεί τη συχνότερη αυτοάνοση δερματοπάθεια του σκύλου, οφείλεται στην παραγωγή αυτοαντισωμάτων κατά των δεσμοσωματίων του άνω τρίτου της επιδερμίδας, με τελικό αποτέλεσματην απώλεια της συνοχής των κερατινοκυττάρων (ακανθολυση) και τη δημιουργία ενδοεπιδερμικών φλυκταινών. Στην εργασία αυτή αναφέρονται η κλινική και η ιστοπαθολογική εικόνα, η θεραπευτική αγωγή και η εξέλιξη πέντε σκύλων με ΦΠ, που ήταν ιδιοπαθής (3/5) ή δευτερογενής υστέρα από χορήγηση τριμεθοπρίμης-σουλφοναμιδών (1/5)και αλλεργικής δερματίτιδας (1/5). Και τα 5 περιστατικά παρουσίαζαν υποτρίχωση-αλωπεκία (4/5), ερύθημα (4/5), φυσαλίδες (1/5), φλύκταινες (5/5), εφελκίδες (5/5), περιφερικήεπιδερμική αποκόλληση (3/5), δρυφάδες (1/5), διαβρώσεις(3/5), έλκη (1/5), συρίγγια (1/5), λειχηνοποίηση, πάχυνση και πτύχωση του δέρματος (1/5) και υπερκεράτωση των πελματικών φυμάτων (1/5). Οι αλλοιώσεις αυτές, που εντοπίζονταν στην κεφαλή (4/5), στα πτερύγια των αυτιών(4/5), στα άκρα (3/5), στον κορμό (3/5) και στα πελματικά φύματα (2/5), ήταν κνησμώδεις στα 3 από τα 5 ζώα. Η διάγνωση στηρίχτηκε στην ιστοπαθολογική εξέταση των βιοψιών από το δέρμα, όπου η πλέον χαρακτηριστική αλλοίωση ήταν οι γεμάτες από φυσιολογικά ουδετερόφιλα και ακανθολυτικά κύτταρα υποκεράτιες φλύκταινες. Επιπλέον στην κυτταρολογική εξέταση του περιεχομένου των φλυκταινών ή των εφελκίδων παρατηρήθηκε μεγάλος αριθμός ακανθολυτικών κυττάρων σε 2 από τους 3 σκύλους. Η θεραπευτική αγωγή που εφαρμόστηκε σε 2 ζώα και είχε πολΰ καλό αποτέλεσμα, περιλάμβανε το συνδυασμό πρεδνιζολόνης σε ανοσοκατασταλτικό σχήμα μαζί με αζαθειοπρίνη (δευτερογενής ΦΠ λόγω αλλεργικής δερματίτιδας), ή εκείνοντης δαψόνης, της οξυτετρακυκλίνης και της βιταμίνης Ε (ιδιοπαθής ΦΠ). Στα υπόλοιπα 3 περιστατικά δεν έγινε κανενός είδους θεραπεία, αφού το πρώτο αυτοϊάθηκε μετά τη διακοπή χορήγησης του υπευθύνου φαρμάκου, ενώ για τα άλλα δυο χάθηκε κάθε επικοινωνία μετά το αποτέλεσμα της ιστοπαθολογικής εξέτασης.Pemphigus folliaceus (PF), which is considered the most common autoimmune skin disease in the dog, is associated with the formation of autoantibodies directed against the desmosomes of the upper third of the epidermis, that result in loss of keratinocyte adhesion (acantholysis) and subsequent epidermal cleft formation. The clinical and histopathological findings, along with the response to treatment in 5 PF cases, either idiopathic (3/5) or secondary to trimethoprim-sulfonamides (1/5) and to allergic dermatitis (1/5), are presented and discussed, accordingly. All the 5 dogs exhibited hypotrichosis-alopecia (4/5), erythema (4/5), vesicles (1/5), pustules (5/5), crusts (5/5), epidermal collarettes (3/5), excoriations (1/5), erosions (3/5), ulcers (1/5), fissures (1/5), lichenification, thickening and folding of the skin (1/5), and footpad hyperkeratosis (1/5), that were pruritic in 3 of them. These lesions were located on the head (4/5), pinnae (4/5), limbs (3/5), body trunk (3/5) and the footpads (2/5). Diagnosis was based on the results of lesionai histopathology where the most striking finding was the presence of subcorneal pustules filled with normally looking neutrophils and acanthocytes. Moreover, pustule or crust cytology that was carried out in 3 cases, revealed clusters of acantholytic cells in 2 dogs. The treatment, that was instituted in 2/5 dogs and resulted in a complete resolution of skin lesions, was based on prednisolone in immunosuppressive dosage along with azathioprine (PF secondary to allergic dermatitis), or on a combination of dapsone, Oxytetracycline and vitamin E (idiopathic PF). The remaining 3 cases were left untreated, because one showed a spontaneous remission following withdrawal of the offending medication and the other 2 were lost to follow-up

Factors that influence inter-organisational integration: a qualitative exploration of service providers' perspectives from an integrated care initiative.

Integrated care uses inter-professional and inter-organisational collaboration to ensure quality care for those with complex healthcare needs. Whilst inter-organisational collaboration is seen as a facilitator of integration, it has its own complexities and challenges. This study sought to investigate barriers to and facilitators of inter-organisational integration between the partnered organisations of an integrated care initiative in Luton, UK, as perceived by healthcare professionals. Face to face semi – structured interviews were conducted between November 2019 and March 2020 with twenty service providers of an integrated service for physical and mental health. Thematic analysis was used to explore the experiences and perceptions of service providers on the integration of healthy lifestyle and mental health services of “Total Wellbeing Luton”. Five primary themes were identified: (1) Culture, (2) Communication Structures, (3) Strategic alignment, (4) Workforce dynamics, and (5) Expectation and reality of the integration. The majority of the identified themes reflect factors that facilitate or impede the integration between the participating organisations. Excellent relationships between healthcare professionals and staff’s motivation have been identified as facilitators to inter-organisational integration, while high staff turnover, lack of shared IT system and absence of co-location have been identified as barriers. Also, a theme reveals that often there was a discrepancy between the expected and the actual implementation and outcomes of integration. As a part of a larger evaluation programme, this study attempts a comprehensive understanding of the inter-organisational integration in the specific context of Total Wellbeing Luton. The findings and recommendations can support the inter-organisational integration of current and future integrated care initiatives in the UK and elsewhere. The online version contains supplementary material available at 10.1186/s12913-025-13051-7.The study is part of a PhD studentship jointly funded by Turning Point, and University of Bedfordshire.gold o

Implementation of step-down Intermediate Care (IC) in Buckinghamshire, UK: a qualitative evaluation study of healthcare professionals' experiences and perspectives

Step-down intermediate care aims to offer short-term care for people who are medically optimised for discharge but needing a period for further assessment and/or rehabilitation. The aim of this study, which was nested in a larger evaluation project, was to explore the experiences and perspectives of healthcare professionals to understand the implementation of a step-down IC service in Buckinghamshire, UK. The evidence is used to inform the service providers of what elements worked well and what areas require improvement. A qualitative study using semistructured interviews was conducted in May 2022. Ten healthcare professionals participated. Interviews were transcribed verbatim and reflexive thematic analysis was used to analyse the data. The following five core themes were developed: (1) the developmental period of step-down IC, (2) providing care together, (3) perceived functions of the integrated hub, (4) communication, and (5) resources. Findings from the interviews highlighted the excellent working relationships among healthcare professionals from different disciplines, which contributed to their job satisfaction and the efficiency of the service. In addition, healthcare professionals stressed the importance of the integrated hub, as it facilitated the communication between the teams and speeded up the decision-making. Several organisational challenges, such as communication issues, healthcare professionals’ capacity, and the need for further funding were also voiced. Involving staff in the evaluation of a step-down intermediate care service has provided useful information on the service’s implementation process and will inform the development of a long-term strategy for intermediate care.Buckinghamshire Healthcare NHS Trustgold o

Evaluating step-down, intermediate care programme in Buckinghamshire, UK: a mixed methods study

Intermediate care (IC) services are models of care that aim to bridge the gap between hospital and home, enabling continuity of care and the transition to the community. The purpose of this study was to explore patient experience with a step-down, intermediate care unit in Buckinghamshire, UK. A mixed-methods study design was used. Twenty-eight responses to a patient feedback questionnaire were analysed and seven qualitative semi-structured interviews were conducted. The eligible participants were patients who had been admitted to the step-down IC unit. Interview transcripts were analysed using thematic analysis. Our interview data generated five core themes: (1) "Being uninformed", (2) "Caring relationships with health practitioners", (3) "Experiencing good intermediate care", (4) "Rehabilitation" and (5) "Discussing the care plan". When comparing the quantitative to the qualitative data, these themes are consistent. Overall, the patients reported that the admission to the step-down care facility was positive. Patients highlighted the supportive relationship they formed with healthcare professionals in the IC and that the rehabilitation that was offered in the IC service was important in increasing mobility and regaining their independence. In addition, patients reported that they were largely unaware about their transfer to the IC unit before this occurred and they were also unaware of their discharge package of care. These findings will inform the evolving patient-centred journey for service development within intermediate care.The study was funded by the Buckinghamshire Healthcare NHS Trust.gold o

Multi-modality curative treatment of salivary gland cancer liver metastases with drug-eluting bead chemoembolization, radiofrequency ablation, and surgical resection: a case report

<p>Abstract</p> <p>Introduction</p> <p>Liver metastases are rare in salivary gland tumors and have been reported only once to be the first manifestation of the disease. They are usually treated with surgical resection of the primary tumor and systemic chemotherapy. Drug-eluting bead chemoembolization has an evolving role in the treatment of hepatocellular carcinoma, as well as in the treatment of metastatic disease of the liver. Nevertheless, it has never been used in a patient with salivary gland liver metastases.</p> <p>Case presentation</p> <p>We report a case of a 51-year-old Caucasian Greek woman who presented to our hospital with liver metastases as the first manifestation of an adenoid cystic carcinoma of the left submandibular gland. The liver lesions were deemed inoperable because of their size and multi-focality and proved resistant to systemic chemotherapy. She was curatively treated with a combination of doxorubicin eluting bead (DC Beads) chemoembolization, intra-operative and percutaneous radiofrequency ablation, and radiofrequency-assisted surgical resection. The patient remained disease-free one year after the surgical resection.</p> <p>Conclusion</p> <p>In conclusion, this complex case is an example of inoperable liver metastatic disease from the salivary glands that was refractory to systemic chemotherapy but was curatively treated with a combination of locoregional therapies and surgery. A multi-disciplinary approach and the adoption of modern radiological techniques produced good results after conventional therapies failed and there were no other available treatment modalities.</p

Retrospective comprehensive analysis of regional lymph node recurrence in breast cancer patients (REASON study).

Randomized trials have progressively enabled the de-escalation of axillary surgery in breast cancer (BC) patients, reducing adverse events without compromising survival. Despite a not negligible rate of residual disease in the axilla after sentinel lymph node (SLN) procedure, the risk of regional lymph node recurrence (RLNR) is very low, due probably to multimodal adjuvant treatments. The characteristics of the small number of patients with RLNR remain poorly characterized and warrant further investigation, especially given their poor prognosis and the current context of ongoing studies exploring further de-escalation of axillary surgery. In this retrospective and single institution study, we analyzed thoroughly a cohort of patients who experienced RLNR as first event between 2009 and 2020. MammaPrint and BluePrint analysis (MB) was performed in available primary invasive cancer tissues. Forty patients, median age of 52, were analyzed. Disease-free interval was 8.7 years. Most of the patients (65%) had no special type BC. Majority (73%) had hormone receptor positive-HER2 negative (HR + /HER2-) BC, 13% triple negative (TNBC), 6% HER2 + , 8% ductal carcinoma in situ and 3% unknown. The median size of the primary tumor was 1.8 cm (range 0.3-7.0) and 57% had no initial LN involvement. Forty five percent had primary SLN procedure and 53% axillary LN dissection (ALND) of the patients received neo-/adjuvant chemotherapy, 63% endocrine therapy and 68% radiotherapy (50% only in breast). Sixty three percent had only RLNR and 38% had concomitant distant metastases. Among irradiated patients, 63% had some relapse in the radiation field. The MB analysis classified 70% of the analyzed cancers as low-risk luminal A (82% in HR + /HER2-), 15% high-risk luminal B, 10% high-risk basal type, and 5% high-risk HER2 type. Our study confirms that patients treated with SLN do not show a higher risk of LRNR compared to ALND. LRNR is often diagnosed incidentally. Younger age, residual disease post-NAC, no regional radiation, stage II, and initial LN involvement were more represented, as well as patients with endocrine sensitive disease classified as low-risk luminal A by MB. Ongoing trials, including SOUND, INSEMA, and BOOG 2013-08, are further exploring axillary surgery de-escalation

An assessment of serum leptin levels in patients with chronic viral hepatitis: a prospective study

<p>Abstract</p> <p>Background</p> <p>The role of leptin in the course of liver disease due to chronic viral hepatitis (CVH) remains controversial. Our aims were to investigate the relationship between serum leptin concentrations and the severity of liver disease in a cohort of subjects with HBeAg negative chronic hepatitis B (CHB) and C (CHC) and to analyze the effect of body composition, the leptin system and insulin resistance together with viral factors on virologic response to antiviral treatment.</p> <p>Methods</p> <p>We studied 50 (36 men) consecutive patients suffering from biopsy-proven CVH due to HBV (n = 25) or HCV (n = 25) infection. Thirty-two (17 men) healthy volunteers served as controls. Levels of serum leptin and insulin were determined by immunoassays at baseline and at the end of the treatment.</p> <p>Results</p> <p>A significant association between serum leptin levels and the stage of hepatic fibrosis was noted; patients with cirrhosis presented higher serum leptin levels compared to those with lower fibrosis stage [CHB patients (17436 pg/ml vs 6028.5 pg/ml, p = 0.03), CHC patients (18014 pg/ml vs 4385 pg/ml, p = 0.05]. An inverse correlation between lower leptin levels and response to lamivudine monotherapy was noted in patients with CHB; those with a virologic response presented lower serum leptin levels (5334 vs 13111.5 pg/ml; p-value = 0.003) than non-responders. In genotype 1 CHC patients, insulin resistance played a significant role in the response to antiviral therapy.</p> <p>Conclusion</p> <p>Our data clearly suggest that cirrhosis due to CHB or CHC is associated with higher leptin levels. Increased serum leptin levels represent a negative prognostic factor for response to lamivudine monotherapy in patients with CHB. In CHC patients insulin resistance strongly influences the response to antiviral treatment in patients infected with genotype 1.</p

Radioactive Holmium Acetylacetonate Microspheres for Interstitial Microbrachytherapy: An In Vitro and In Vivo Stability Study

Purpose The clinical application of holmium acetylacetonate microspheres (HoAcAcMS) for the intratumoral radionuclide treatment of solid malignancies requires a thorough understanding of their stability. Therefore, an in vitro and an in vivo stability study with HoAcAcMS was conducted. Methods HoAcAcMS, before and after neutron irradiation, were incubated in a phosphate buffer at 37°C for 6 months. The in vitro release of holmium in this buffer after 6 months was 0.5%. Elemental analysis, scanning electron microscopy, infrared spectroscopy and time of flight secondary ion mass spectrometry were performed on the HoAcAcMS. Results After 4 days in buffer the acetylacetonate ligands were replaced by phosphate, without altering the particle size and surface morphology. HoAcAcMS before and after neutron irradiation were administered intratumorally in VX2 tumor-bearing rabbits. No holmium was detected in the faeces, urine, femur and blood. Histological examination of the tumor revealed clusters of intact microspheres amidst necrotic tissue after 30 days. Conclusion HoAcAcMS are stable both in vitro and in vivo and are suitable for intratumoral radionuclide treatment.Radiation, Radionuclides and ReactorsApplied Science