Assembly of infectious Kaposi's sarcoma-associated herpesvirus progeny requires formation of a pORF19 pentamer.

Herpesviruses cause severe diseases particularly in immunocompromised patients. Both genome packaging and release from the capsid require a unique portal channel occupying one of the 12 capsid vertices. Here, we report the 2.6 Å crystal structure of the pentameric pORF19 of the γ-herpesvirus Kaposi's sarcoma-associated herpesvirus (KSHV) resembling the portal cap that seals this portal channel. We also present the structure of its ß-herpesviral ortholog, revealing a striking structural similarity to its α- and γ-herpesviral counterparts despite apparent differences in capsid association. We demonstrate pORF19 pentamer formation in solution and provide insights into how pentamerization is triggered in infected cells. Mutagenesis in its lateral interfaces blocked pORF19 pentamerization and severely affected KSHV capsid assembly and production of infectious progeny. Our results pave the way to better understand the role of pORF19 in capsid assembly and identify a potential novel drug target for the treatment of herpesvirus-induced diseases.

Oclacitinib therapy in two cats with refractory proliferative and necrotising otitis externa.

Feline proliferative and necrotising otitis externa (PNOE) is a rare immune-mediated condition, usually self-limiting or responsive to immunosuppressants such as topical tacrolimus. This case report describes two cats with refractory PNOE that responded successfully to oclacitinib. One cat also had middle ear involvement and the other cat had extra-auricular dermatitis.

Local treatment for canine anal sacculitis: A retrospective study of 33 dogs.

BACKGROUND: Little information has been published regarding treatment of canine anal sacculitis (AS). OBJECTIVES: Primary objective: determine the outcomes of AS local treatment at the referral dermatology service of the authors' institution. SECONDARY OBJECTIVE: determine signalment, body condition score (BCS), stool quality and comorbidities associated with AS. ANIMALS: Thirty-three dogs with AS presented to the referral dermatology service between 1 January 2010 and 31 March 2021. MATERIALS AND METHODS: An electronic medical record search was conducted. Information regarding sex, breed, age at disease onset, weight, BCS, stool quality, comorbidities, treatment and treatment outcome were collected. Treatment outcome was categorised as "resolved clinically", "clinical signs resolved per owner", "did not complete treatment" or "failed". Dogs were excluded if seen by another service, not treated for AS, or if perianal sinuses (fistulae), anal sac masses, or anal sac abscesses were identified. RESULTS: Nineteen dogs were male and 14 female. Twenty-four breeds were included. Average age at disease onset was 4.4 years. Average BCS was 5.8 of 9. Stool quality was "poor" in seven of 33 and normal in 23 of 33 cases. Atopic dermatitis was the most common comorbidity (12 of 33). Treatment typically consisted of anal sac flushing with saline followed by infusion using a commercially available steroid/antibiotic/antifungal ointment. Treatment was repeated on average 2.9 times. Resolution of AS was obtained in 24 of 33 cases, clinical signs resolved per owner in four of 33, five of 33 cases did not complete treatment, and no cases failed treatment. CONCLUSIONS AND CLINICAL RELEVANCE: Local treatment with flushing and infusion is effective for treating AS in dogs.

Contexte - Peu d'informations ont été publiées concernant le traitement de la sacculite anale canine (SA). Objectifs - Objectif principal : déterminer les résultats du traitement local de la SA au service de dermatologie des auteurs. Objectif secondaire : déterminer le signalement, le score d'état corporel (BCS), la qualité des selles et les comorbidités associées à la SA. Animaux - Trente-trois chiens SA présentés au service de dermatologie entre le 1er janvier 2010 et le 31 mars 2021. Matériels et méthodes - Une recherche dans le dossier médical électronique a été effectuée. Des informations concernant le sexe, la race, l'âge au début de la maladie, le poids, le BCS, la qualité des selles, les comorbidités, le traitement et les résultats du traitement ont été recueillies. Le résultat du traitement a été classé comme « résolu cliniquement ¼, « signes cliniques résolus par le propriétaire ¼, « n'a pas terminé le traitement ¼ ou « échec ¼. Les chiens ont été exclus s'ils étaient vus par un autre service, non traités pour la SA, ou si des sinus périanaux (fistules), des masses du sac anal ou des abcès du sac anal étaient identifiés. Résultats - Dix-neuf chiens étaient des mâles et 14 des femelles. Vingt-quatre races ont été incluses. L'âge moyen au début de la maladie était de 4,4 ans. Le BCS moyen était de 5,8 sur 9. La qualité des selles était « mauvaise ¼ dans sept cas sur 33 et normale dans 23 cas sur 33. La dermatite atopique était la comorbidité la plus fréquente (12 sur 33). Le traitement consistait généralement en un rinçage du sac anal avec une solution saline suivi d'une perfusion à l'aide d'une pommade stéroïde/antibiotique/antifongique disponible dans le commerce. Le traitement a été répété en moyenne 2,9 fois. La résolution de la SA a été obtenue dans 24 des 33 cas, les signes cliniques ont disparu dans quatre des 33 cas, cinq des 33 cas n'ont pas terminé le traitement et aucun cas n'a échoué au traitement. Conclusions et pertinence clinique - Le traitement local par rinçage et perfusion est efficace pour traiter la SA chez le chien.

Introducción- se ha publicado poca información sobre el tratamiento de la saculitis anal canina (AS). Objetivos - Objetivo primario: determinar los resultados del tratamiento local de la AS en el servicio de referencia dermatológica de la institución de los autores. Objetivo secundario: determinar la presentación clínica, la puntuación de la condición corporal (BCS), la calidad de las heces y las comorbilidades asociadas a la AS. Animales - Treinta y tres perros con AS presentados al servicio de dermatología de referencia entre el 1 de enero de 2010 y el 31 de marzo de 2021. Materiales y métodos - Se realizó una búsqueda en la historia clínica electrónica. Se recopiló información sobre sexo, raza, edad de inicio de la enfermedad, peso, BCS, calidad de las heces, comorbilidades, tratamiento y resultado del tratamiento. El resultado del tratamiento se clasificó como "resuelto clínicamente", "signos clínicos resueltos por propietario", "no completó el tratamiento" o "fracasó". Los perros fueron excluidos si fueron vistos por otro servicio, no tratados por AS, o si se identificaron senos perianales (fístulas), masas en los sacos anales o abscesos en los sacos anales. Resultados- diecinueve perros eran machos y 14 hembras. Se incluyeron veinticuatro razas. La edad promedio de inicio de la enfermedad fue de 4,4 años. BCS promedio fue 5.8 de 9. La calidad de las heces fue "mala" en siete de 33 y normal en 23 de 33 casos. La dermatitis atópica fue la comorbilidad más común (12 de 33). El tratamiento generalmente consistía en enjuagar el saco anal con solución salina seguido de una infusión usando un ungüento de esteroide/antibiótico/antifúngico disponible en el mercado. El tratamiento se repitió un promedio de 2,9 veces. La resolución de AS se obtuvo en 24 de 33 casos, los signos clínicos se resolvieron por propietario en cuatro de 33, cinco de 33 casos no completaron el tratamiento y ningún caso fracasó en el tratamiento. Conclusiones y relevancia clínica- el tratamiento local con lavado e infusión intrasacular es eficaz para tratar la AS en perros.

Contexto - Poucas informações foram publicadas sobre o tratamento da saculite anal (SA) canina. Objetivos - Objetivo primário: determinar os desfechos do tratamento tópico localizado da SA em um serviço especializado de dermatologia veterinária da instituição do autor. Objetivo secundário: determinar as manifestações clínicas, escore de condição corporal (ECC), qualidade das fezes e comorbidades associadas à SA. Animais - Trinta e três cães com SA apresentados ao serviço de dermatologia entre 1° de janeiro de 2010 e 39 de março de 2021. Materiais e métodos - Realizou-se um levantamento de prontuários eletrônicos. Foram coletadas informações sobre sexo, raça, idade no surgimento da doença, peso, ECC, qualidade das fezes, comorbidades, tratamentos e desfecho do tratamento. O desfecho do tratamento foi categorizado como "resolvido clinicamente", "sinais clínicos resolvidos de acordo com o tutor", "não completou o tratamento" ou "falhou". Os cães foram excluídos do estudo se tivessem sido tratados em outro serviço, não tivessem sido tratados para SA, ou se fossem identificados abscessos, massas ou fístulas nos sacos anais. Resultados - Dezenove cães eram machos e 14 fêmeas. Vinte e quatro raças foram incluídas. A idade média no surgimento da doença foi de 4,4 anos. O ECC médio foi 5,8 em 9. A qualidade das fezes foi ruim em sete de 33 cães e normal em 22 de 33 casos. A dermatite atópica foi a comorbidade mais comum (12 de 33). O tratamento tipicamente consistiu de lavagem dos sacos anais com solução salina seguido de infusão de uma solução comercial contendo esteroide/antibiótico/antifúngico. O tratamento foi repetido em média 2,9 vezes. Resolução da SA foi alcançada em 24 de 33 casos, os sinais clínicos se resolveram de acordo com o tutor em quatro de 33 casos, cinco de 33 casos não completaram o tratamento e em nenhum caso houve falha terapêutica. Conclusões e relevância clínica - Tratamento tópico com lavagem e infusão é eficaz para tratar SA em cães.

Validation of the 0-10 verbal numeric scale for assessment of pruritus severity in dogs.

BACKGROUND: The pruritus Visual Analog Scale (pVAS) is currently the only validated tool for assessing canine pruritus. A verbal numeric scale (VNS) offers an alternative if clients are not present or able to complete the pVAS. HYPOTHESIS/OBJECTIVE: To validate the 0-10 VNS and evaluate its interchangeability with the pVAS. ANIMALS: 251 dogs were included in the study. MATERIALS AND METHODS: Dog owners were asked to assess their pet's pruritus level using the pVAS, the 0-10 VNS and the verbal rating categories (mild, moderate, severe) in one or two subsequent visits. To be valid, VNS must satisfy the following: correlate with pVAS (criterion validity); indicate reduction in itch score after an antipruritic intervention (construct validity); and have scores related to the verbal rating categories that are significantly different (content validity). VNS and pVAS interchangeability and the percentage of clients that preferred the VNS and pVAS also were evaluated. RESULTS: The VNS and pVAS correlation for visits 1 and 2 was good (rICC = 0.9) and excellent (rICC = 0.94). The VNS scores were significantly decreased after antipruritic interventions (P < 0.001). The VNS scores associated with the verbal rating scale categories (mild, moderate and severe) were significantly different (P < 0.001). The 95% limits of agreement for the pVAS and VAS were outside the limit of acceptability of ±2 (-2.0, 2.57). Most clients (69%) preferred the pVAS to the VNS. CONCLUSIONS AND CLINICAL RELEVANCE: The VNS is a valid scale to evaluate canine pruritus; however, the VNS and pVAS are not interchangeable.

Targeting Kaposi's Sarcoma-Associated Herpesvirus ORF21 Tyrosine Kinase and Viral Lytic Reactivation by Tyrosine Kinase Inhibitors Approved for Clinical Use.

Kaposi's sarcoma-associated herpesvirus (KSHV) is the cause of three human malignancies: Kaposi's sarcoma, primary effusion lymphoma, and the plasma cell variant of multicentric Castleman disease. Previous research has shown that several cellular tyrosine kinases play crucial roles during several steps in the virus replication cycle. Two KSHV proteins also have protein kinase function: open reading frame (ORF) 36 encodes a serine-threonine kinase, while ORF21 encodes a thymidine kinase (TK), which has recently been found to be an efficient tyrosine kinase. In this study, we explore the role of the ORF21 tyrosine kinase function in KSHV lytic replication. By generating a recombinant KSHV mutant with an enzymatically inactive ORF21 protein, we show that the tyrosine kinase function of ORF21/TK is not required for the progression of the lytic replication in tissue culture but that it is essential for the phosphorylation and activation to toxic moieties of the antiviral drugs zidovudine and brivudine. In addition, we identify several tyrosine kinase inhibitors, already in clinical use against human malignancies, which potently inhibit not only ORF21 TK kinase function but also viral lytic reactivation and the development of KSHV-infected endothelial tumors in mice. Since they target both cellular tyrosine kinases and a viral kinase, some of these compounds might find a use in the treatment of KSHV-associated malignancies.IMPORTANCE Our findings address the role of KSHV ORF21 as a tyrosine kinase during lytic replication and the activation of prodrugs in KSHV-infected cells. We also show the potential of selected clinically approved tyrosine kinase inhibitors to inhibit KSHV TK, KSHV lytic replication, infectious virion release, and the development of an endothelial tumor. Since they target both cellular tyrosine kinases supporting productive viral replication and a viral kinase, these drugs, which are already approved for clinical use, may be suitable for repurposing for the treatment of KSHV-related tumors in AIDS patients or transplant recipients.

Kaposi's sarcoma-associated herpesvirus vIRF2 protein utilizes an IFN-dependent pathway to regulate viral early gene expression.

Kaposi's sarcoma-associated herpesvirus (KSHV; human herpesvirus 8) belongs to the subfamily of Gammaherpesvirinae and is the etiological agent of Kaposi's sarcoma as well as of two lymphoproliferative diseases: primary effusion lymphoma and multicentric Castleman disease. The KSHV life cycle is divided into a latent and a lytic phase and is highly regulated by viral immunomodulatory proteins which control the host antiviral immune response. Among them is a group of proteins with homology to cellular interferon regulatory factors, the viral interferon regulatory factors 1-4. The KSHV vIRFs are known as inhibitors of cellular interferon signaling and are involved in different oncogenic pathways. Here we characterized the role of the second vIRF protein, vIRF2, during the KSHV life cycle. We found the vIRF2 protein to be expressed in different KSHV positive cells with early lytic kinetics. Importantly, we observed that vIRF2 suppresses the expression of viral early lytic genes in both newly infected and reactivated persistently infected endothelial cells. This vIRF2-dependent regulation of the KSHV life cycle might involve the increased expression of cellular interferon-induced genes such as the IFIT proteins 1, 2 and 3, which antagonize the expression of early KSHV lytic proteins. Our findings suggest a model in which the viral protein vIRF2 allows KSHV to harness an IFN-dependent pathway to regulate KSHV early gene expression.

Structural aspects of the aging invertebrate brain.

Aging is characterized by a decline in neuronal function in all animal species investigated so far. Functional changes are accompanied by and may be in part caused by, structurally visible degenerative changes in neurons. In the mammalian brain, normal aging shows abnormalities in dendrites and axons, as well as ultrastructural changes in synapses, rather than global neuron loss. The analysis of the structural features of aging neurons, as well as their causal link to molecular mechanisms on the one hand, and the functional decline on the other hand is crucial in order to understand the aging process in the brain. Invertebrate model organisms like Drosophila and C. elegans offer the opportunity to apply a forward genetic approach to the analysis of aging. In the present review, we aim to summarize findings concerning abnormalities in morphology and ultrastructure in invertebrate brains during normal aging and compare them to what is known for the mammalian brain. It becomes clear that despite of their considerably shorter life span, invertebrates display several age-related changes very similar to the mammalian condition, including the retraction of dendritic and axonal branches at specific locations, changes in synaptic density and increased accumulation of presynaptic protein complexes. We anticipate that continued research efforts in invertebrate systems will significantly contribute to reveal (and possibly manipulate) the molecular/cellular pathways leading to neuronal aging in the mammalian brain.

Cost evaluation of PAGE-B risk score guided HCC surveillance in patients with treated chronic hepatitis B.

BACKGROUND: The PAGE-B score (Platelet Age GEnder-HBV) selects chronic hepatitis B (cHB) patients showing no relevant 5-year risk for hepatocellular carcinoma (HCC). We, therefore, explored potential cost reduction following the introduction of a PAGE-B tailored ultrasound screening in a single center cohort of cHB patients receiving stable antiviral therapy. METHODS: cHB patients attending throughout the year 2018 were documented. Patients eligible for PAGE-B score were classified into high (≥18 points), intermediate (10-17 points) and low (≤9 points) HCC risk groups. Patients of the low HCC risk group could postpone HCC screening to reduce HCC screening expenses. Full costs for hepatic ultrasound were assessed. RESULTS: Throughout the year cHB patients (n = 607) attended our clinic, which included PAGE-B eligible patients (n = 227, 37.4%) of whom n = 94 (15.8%) were allocated to the low HCC risk group. Sonographic HCC screening during a median exam time of 12.4 min (IQR 9.2-17.2) resulted in total costs of 22.82 Euro/exam. Additional opportunistic expenses caused by patient's lost earnings or productivity were 15.6-17.5 €/exam and 26.7 €/exam, respectively. Following a PAGE-B tailored HCC screening at our institution annual full costs for cHB patients could be reduced by 15.51%, which equals a cost reduction by 1.91% for our total sonography unit. In comparison, 1.35% up to 7.65% of HBV-infected patients of Caucasian descent could postpone HCC screening according to population-based estimates from Germany. CONCLUSIONS: PAGE-B risk score adapted screening for HCC is an efficient and cost neutral tool to reduce costs for sonography in Caucasian patients with chronic hepatitis B receiving antiviral treatment.

The biology of human hair: A multidisciplinary review.

In the last century, human scalp hair morphology has been studied from multiple, and sometimes mutually exclusive, perspectives by anthropologists, biologists, geneticists, forensic scientists, and cosmetic scientists. Here, we review and synthesize historical and current research on hair to better understand the scientific basis and biological implications of hair microstructure and morphology. We revisit the origins of existing nomenclature regarding hair morphology and classifications, discuss the currently recognized limitations to hair analysis within the varied scientific disciplines studying hair, point out aspects of hair biology that remain unknown, and the great potential for integrating these diverse perspectives and expertise in future scientific investigations, while highlighting the benefits of combining nondestructive microscopical analysis with chemical and genomic analyses for explicating hair biology. Further, we propose consensus terminology for root growth stages through descriptions and images that will aid in the morphological and microscopical analysis of human scalp hair, thereby reducing confusion and the promulgation of inaccurate information that is presently in the literature.

Patulous Eustachian tube and palatine defect in a Dachshund with chronic unilateral otitis externa and otitis media.

BACKGROUND: Patulous Eustachian tube (pET) is a rare dysfunction of the Eustachian tube described in humans. It is characterized by failure of the ET to close, resulting in unrestricted passage of air, sound and material between the nasopharynx and the middle ear. OBJECTIVE: To report a case of pET associated with otitis in a dog. ANIMAL: A 6-year old-female spayed Dachshund dog. METHODS AND MATERIALS: Otoscopic examination, cytological evaluation, culture and susceptibility, computerized tomography (CT), video-otoscopic flushing and surgery. RESULTS: Left ear otoscopic examination revealed erythema, purulent frothy discharge, ceruminous gland hyperplasia, stenosis and a partial tear of the tympanum. Cytological evaluation from the left external canal showed neutrophils, macrophages, rods and cocci. Aerobic culture showed predominantly multidrug-resistant Pseudomonas aeruginosa. The CT findings of the left ear included chronic changes in the external canal, marked lysis of the tympanic bulla and marked dilation of the ET. During video-otoscope flushing, saline drained through the mouth. Bilateral incomplete hypoplasia of the soft palate was noted. Total ear canal ablation and bulla osteotomy with ET dissection were curative. Histopathological findings were compatible with chronic otitis externa (OE) and media. CONCLUSION AND CLINICAL IMPORTANCE: To the best of the authors' knowledge, this is the first case of pET described in animals. The ET dysfunction and palatine defect were likely the cause of the otitis in this dog. Clinicians should investigate pET in animals with signs of OE characterized by frothy liquid and food fragments in the ear canal in addition to sneezing after drinking water.

Variation in human hair ultrastructure among three biogeographic populations.

Human scalp hairs are often examined microscopically to study the variation and diversity among a range of visible morphological traits. In this study, we focused on the ultrastructure of human scalp hair within its keratinized matrix, emphasizing, the density and distribution of melanosomes, variation in cuticle thickness within populations, and the relationship of hair fiber ultrastructure with biogeographic ancestry. We used transmission electron microscopy (TEM) to visualize hair cross-sections and generate micron-scale resolution images for analysis of particle morphology and the layered hair matrix. Our results revealed considerable variation in all parameters examined, including the relationship of ultrastructure to biogeographic ancestry. Among the three metapopulations studied (European, African, and East Asian), we identified hair cross-sectional shape, cuticle dimensions, and melanosome distribution as traits that reveal statistically significant ancestry-related patterns. This study establishes trait patterns in hair morphology and ultrastructure among three biogeographically defined metapopulations to improve the current understanding of human variation in hair form and establish a foundation for future studies on the genetic and developmental bases of phenotypic variation in hair ultrastructure related to genotype.

Kaposi Sarcoma Herpesvirus (KSHV) Latency-Associated Nuclear Antigen (LANA) recruits components of the MRN (Mre11-Rad50-NBS1) repair complex to modulate an innate immune signaling pathway and viral latency.

Kaposi Sarcoma Herpesvirus (KSHV), a γ2-herpesvirus and class 1 carcinogen, is responsible for at least three human malignancies: Kaposi Sarcoma (KS), Primary Effusion Lymphoma (PEL) and Multicentric Castleman's Disease (MCD). Its major nuclear latency protein, LANA, is indispensable for the maintenance and replication of latent viral DNA in infected cells. Although LANA is mainly a nuclear protein, cytoplasmic isoforms of LANA exist and can act as antagonists of the cytoplasmic DNA sensor, cGAS. Here, we show that cytosolic LANA also recruits members of the MRN (Mre11-Rad50-NBS1) repair complex in the cytosol and thereby inhibits their recently reported role in the sensing of cytoplasmic DNA and activation of the NF-κB pathway. Inhibition of NF-κB activation by cytoplasmic LANA is accompanied by increased lytic replication in KSHV-infected cells, suggesting that MRN-dependent NF-κB activation contributes to KSHV latency. Cytoplasmic LANA may therefore support the activation of KSHV lytic replication in part by counteracting the activation of NF-κB in response to cytoplasmic DNA. This would complement the recently described role of cytoplasmic LANA in blocking an interferon response triggered by cGAS and thereby promoting lytic reactivation. Our findings highlight a second point at which cytoplasmic LANA interferes with the innate immune response, as well as the importance of the recently discovered role of cytoplasmic MRN complex members as innate sensors of cytoplasmic DNA for the control of KSHV replication.

Extent of portal vein tumour thrombosis in patients with hepatocellular carcinoma: The more, the worse?

BACKGROUND & AIMS: Portal vein tumour thrombosis (PVTT) has a significant impact on the prognosis of patients with hepatocellular carcinoma (HCC). The degree of PVTT varies from sub-/segmental invasion to complete occlusion of the main trunk. Aim of this study was to evaluate whether the degree of PVTT correlates with prognosis. METHODS: A total of 1317 patients with HCC treated at our tertiary referral centre between January 2005 and December 2016 were included. PVTT was diagnosed by contrast-enhanced computed tomography or magnetic resonance imaging. The extent of PVTT was documented according to the Liver Cancer Study Group of Japan classification: Vp0 = no PVTT, Vp1 = segmental portal vein invasion, Vp2 = right anterior/posterior portal vein, Vp3 = right/left portal vein and Vp4 = main trunk. Median overall survival (OS) was calculated for each group. RESULTS: Portal vein tumour thrombosis was present in 484 (36.8%) patients. Median OS without PVTT was 35.7 months, significantly longer than in patients with PVTT (7.2 months, P < 0.001). The patients with PVTT were subclassified as follows: 103 Vp1, 87 Vp2, 143 Vp3 and 151 Vp4. The corresponding median OS yielded 14.6, 9.4, 5.8 and 4.8 months for Vp1-Vp4, respectively (P < 0.001). CONCLUSIONS: Portal vein tumour thrombosis in patients with HCC is associated with a dismal prognosis. The results indicate an association between the extent of PVTT and OS. However, the extent of PVTT is not that decisive, as even minor PVTT leads to a very poor prognosis. Therefore, meticulous evaluation of cross-sectional imaging is crucial for the clinical management of patients with HCC.

Treatment with metformin is associated with a prolonged survival in patients with hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) is one of the most lethal cancers. Nutrition- and life style-associated risk factors are increasingly prevalent. Metformin, the mainstay of type 2 diabetes mellitus (T2DM)-treatment, reduces the risk of hepatocarcinogenesis. However, its influence on the prognosis of patients with HCC has not been investigated on a large scale, yet. METHODS: Five thousand and ninety-three patients treated for HCC between 2000 and 2016 at three referral centres were included in this retrospective multicentre study. The aim of this study was to assess whether treatment with metformin for T2DM is associated with a prolonged overall survival (OS) in patients diagnosed with HCC. RESULTS: Among 5093 patients with HCC, 1917 patients (37.6%) were diagnosed with T2DM, of which 338 (17.6%) received treatment with metformin. Compared to diabetic patients not treated with metformin, patients on metformin had a significantly better hepatic function (Child-Pugh-Score A: 69.2% vs 47.4%, P < 0.001) and underwent significantly more often tumour resection (22.1% vs 16.5%, P = 0.024). Patients on metformin had a significantly longer median OS (mOS) compared to diabetic patients not treated with metformin (22 vs 15 months, P = 0.019). The prolongation of survival was most significant in patients treated with surgery. Using a propensity score match (PSM), patients were adjusted for hepatic function and initial therapy. In the matched cohorts, mOS remained significantly longer in metformin-treated patients (22 vs 16 months, P = 0.021). Co-treatment of metformin and sorafenib was associated with a survival disadvantage. CONCLUSION: Treatment with metformin was associated with an improved survival in patients with T2DM and HCC. This effect was most pronounced in patients at potentially curative tumour stages.

Dermal arteritis of the nasal philtrum: a retrospective study of 23 dogs.

BACKGROUND: Dermal arteritis of the nasal philtrum (DANP) is a cutaneous vascular condition that selectively targets large vessels of the nasal philtrum of dogs; little information is published about this disease. OBJECTIVE: The aim of this study was to report the signalment, clinical signs, treatment options and outcome of dogs with DANP, and to propose a rationale for the clinical diagnosis. ANIMALS: Twenty-three dogs from four referral veterinary clinics from January 2002 to July 2018. METHODS AND MATERIALS: Retrospective analysis of medical records of dogs with diagnosis of DANP. RESULTS: The mean age at disease onset was 5.3 years. Nineteen dogs were pure-bred (11 different breeds) and four were mixed breed. Twenty-three dogs had a clinical diagnosis of DANP and three of these had histopathological confirmation. Eight dogs had episodes of profuse arterial bleeding from the lesion, nine had minor bleeding and six no bleeding. Twenty dogs were managed medically with monotherapy or combined therapy of topical tacrolimus, prednisolone, doxycycline and niacinamide, and/or pentoxifylline. Long-term tacrolimus was prescribed for 15 cases, eight of those cases as sole therapy. Treatment was declined for three dogs and four dogs were lost to follow-up. The lesion was satisfactorily controlled in 12 dogs and well-controlled in four dogs. CONCLUSIONS AND CLINICAL IMPORTANCE: The distinctive presentation of DANP substantiates the clinical diagnosis. Medical treatment seems to be effective in controlling DANP and tacrolimus used as sole or adjunctive therapy appears to manage the disease satisfactorily.

Comparison of demographic data, disease severity and response to treatment, between dogs with atopic dermatitis and atopic-like dermatitis: a retrospective study.

BACKGROUND: Limited information is available describing the features of canine atopic-like dermatitis (ALD) compared with atopic dermatitis (AD). OBJECTIVES: To compare demographic data, disease severity and response to therapy between ALD and AD dogs. ANIMALS: Two hundred and fifty-three atopic dogs with intradermal and serum allergen-specific IgE test results were selected retrospectively. METHODS AND MATERIALS: Dogs were enrolled into the ALD group if both IgE tests were negative and into the AD group if at least one test was positive. Demographic data, pruritus level and number of body sites affected before and during therapy, in addition to maintenance therapy protocols, were compared between groups. RESULTS: There were 216 (85.38%) dogs in the AD group and 37 (14.62%) in the ALD group. The soft-coated wheaten terrier, American Staffordshire terrier, English bulldog and Labrador retriever were over-represented in the AD group. No significant differences between the groups were noted regarding the other demographic variables evaluated. There were no differences in the mean pruritus scores and number of affected body sites at the first visit or during treatment. Furthermore, no significant differences between the groups were noted for the maintenance treatment scores and reduction of pruritus level and number of body sites affected during treatment. CONCLUSIONS AND CLINICAL SIGNIFICANCE: The soft-coated wheaten terrier, American Staffordshire terrier, English bulldog and Labrador retriever were over-represented in the AD group. No significant differences in the other demographic data and clinical features were noted between dogs with ALD and AD in the present study.

Canine Pruritus Visual Analog Scale: how does it capture owners' perception of their pet's itching level?

BACKGROUND: Accurate measurement of pruritus severity is difficult in veterinary medicine. OBJECTIVES: To determine how the changes in Pruritus Visual Analog Scale (PVAS) scores at follow-up visits agree with the owners' perceptions of improvement of their pet's pruritus. ANIMALS: One hundred and ninety two pruritic dogs were included in the prospective study and 196 in the retrospective study. METHODS AND MATERIALS: Owners were randomly assigned into five groups and PVAS scores were recorded during two consecutive visits. Group A: previous scores were shown before completing the PVAS; Group B: PVAS was completed then owners were shown previous scores and asked to repeat the PVAS; Group C: PVAS was completed as reported previously; Group D: PVAS and a 0-10 verbal scale (VS) were completed. Retrospectively, PVAS scores were analysed during at least three consecutive visits. The average percentage and kappa agreements were calculated for all groups. In addition, PVAS and VS scores were compared in Group D. RESULTS: The average percentage and kappa agreements were higher in groups A (96%; 0.81), B [before (80%; 0.54), after (82%; 0.59) previous score] and D (85%; 0.47). Group C (79%; 0.37) had the lowest agreement. PVAS and VS scores were not significantly different (P = 0.56) in Group D. The average percentage and kappa agreements for the retrospective study were 50.8% and 0.25. The highest values (63%; 0.355) were noted at 30-60 day visit intervals. CONCLUSIONS AND CLINICAL IMPORTANCE: Showing owners previous scores could improve how PVAS captures the owner's perception of their dog's itching level.

Molecular mechanisms of xeroderma pigmentosum (XP) proteins.

Nucleotide excision repair (NER) is a highly versatile and efficient DNA repair process, which is responsible for the removal of a large number of structurally diverse DNA lesions. Its extreme broad substrate specificity ranges from DNA damages formed upon exposure to ultraviolet radiation to numerous bulky DNA adducts induced by mutagenic environmental chemicals and cytotoxic drugs used in chemotherapy. Defective NER leads to serious diseases, such as xeroderma pigmentosum (XP). Eight XP complementation groups are known of which seven (XPA-XPG) are caused by mutations in genes involved in the NER process. The eighth gene, XPV, codes for the DNA polymerase ɳ, which replicates through DNA lesions in a process called translesion synthesis (TLS). Over the past decade, detailed structural information of these DNA repair proteins involved in eukaryotic NER and TLS have emerged. These structures allow us now to understand the molecular mechanism of the NER and TLS processes in quite some detail and we have begun to understand the broad substrate specificity of NER. In this review, we aim to highlight recent advances in the process of damage recognition and repair as well as damage tolerance by the XP proteins.

Validation of insulin-like growth factor-1 as a prognostic parameter in patients with hepatocellular carcinoma in a European cohort.

BACKGROUND: In hepatocellular carcinoma (HCC), the third leading cause of cancer-related mortality worldwide, the Child-Turcotte-Pugh score (CTP) is one of the most established tools to assess hepatic reserve and determine survival. Serum levels of insulin-like growth factor-1 (IGF-1) are decreased in patients with chronic liver disease or HCC. A modified score combining circulating IGF-1 with the CTP score (IGF-CTP) was recently proposed. METHODS: IGF-CTP scoring was evaluated in 216 patients diagnosed with HCC between 2007 and 2017 to assess the predictive value of serum IGF-1 levels for patient risk stratification and overall survival (OS). RESULTS: Liver cirrhosis was identified in 80.1% of the study cohort, and alcohol-induced liver disease was the most frequent underlying cause of HCC (44.4%). Serum IGF-1 levels were significantly lower in patients with HCC in cirrhosis compared with non-cirrhotic HCC (p < 0.01). A lower serum level of IGF-1 was associated with more advanced stages of liver cirrhosis (p < 0.05) and cancer stages (p < 0.001). Median OS in the cohort was 11.4 months (range 0.5-118.2 months). OS was significantly higher (10.9 vs. 7.9 months; p < 0.05) in patients with a serum IGF-1 level above the median of 43.4 ng/mL. Patient reassignment using IGF-CTP scoring reclassified 35.6% of patients. Through reassignment, stratification regarding OS was comparable to CTP. CONCLUSIONS: This study is the first to investigate IGF-1 and the IGF-CTP classification in a European cohort of HCC patients. Serum IGF-1 correlates with OS in patients with HCC. However, the IGF-CTP classification was not superior compared to CTP score regarding OS.

Validation of the SNACOR clinical scoring system after transarterial chemoembolisation in patients with hepatocellular carcinoma.

BACKGROUND: Transarterial chemoembolisation is the standard of care for intermediate stage (BCLC B) hepatocellular carcinoma, but it is challenging to decide when to repeat or stop treatment. Here we performed the first external validation of the SNACOR (tumour Size and Number, baseline Alpha-fetoprotein, Child-Pugh and Objective radiological Response) risk prediction model. METHODS: A total of 1030 patients with hepatocellular carcinoma underwent transarterial chemoembolisation at our tertiary referral centre from January 2000 to December 2016. We determined the following variables that were needed to calculate the SNACOR at baseline: tumour size and number, alpha-fetoprotein level, Child-Pugh class, and objective radiological response after the first transarterial chemoembolisation. Overall survival, time-dependent area under receiver-operating characteristic curves, Harrell's C-index, and the integrated Brier score were calculated to assess predictive ability. Finally, multivariate analysis was performed to identify independent predictors of survival. RESULTS: The study included 268 patients. Low, intermediate, and high SNACOR scores predicted a median survival of 31.5, 19.9, and 9.2 months, respectively. The areas under the receiver-operating characteristic curve for overall survival were 0.641, 0.633, and 0.609 at 1, 3, and 6 years, respectively. Harrell's C-index was 0.59, and the integrated Brier Score was 0.175. Independent predictors of survival included tumour size (P < 0.001), baseline alpha-fetoprotein level (P < 0.001) and Child-Pugh class (P < 0.004). Objective radiological response (P = 0.821) and tumour number (P = 0.127) were not additional independent predictors of survival. CONCLUSIONS: The SNACOR risk prediction model can be used to identify patients with a dismal prognosis after the first transarterial chemoembolisation who are unlikely to benefit from further transarterial chemoembolisation. However, Harrell's C-index showed only moderate performance. Accordingly, this risk prediction model can only serve as one of several components used to make the decision about whether to repeat treatment.