The Diversification of Cell Death and Immunity: Memento Mori.

Why do cells have so many ways to die? Why does "cellular suicide" exist at all? In the war against pathogens and rogue cells, organisms developed cellular suicide as a last resort. Fighting an evolutionary arms race, cell death pathways have adapted and multiplied to cover the complexity of the foes the immune system faces. In this review, we discuss the different types of cell death, the underlying signaling events, and their unequal ability to trigger an immune response. We also comment on how to use our knowledge of cell death signaling to improve the efficacy of cancer treatment. We argue that cell death is integral to the immune response and acts as a beacon, a second messenger, that guides both immune system and tissue micro-environment to ensure tissue repair and homeostasis. Memento mori-"remember you must die"-as failure to do so opens the way to chronic infection and cancer.

Omalizumab in the treatment of bullous pemphigoid resistant to first-line therapy: a French national multicentre retrospective study of 100 patients.

BACKGROUND: Interest in the use of omalizumab to treat bullous pemphigoid (BP) in the event of resistance or contraindication to conventional therapies is currently based on limited evidence. OBJECTIVES: To assess the effectiveness and safety of omalizumab in BP and to identify predictive factors in response to treatment. METHODS: We conducted a French national multicentre retrospective study including patients with a confirmed diagnosis of BP treated with omalizumab after failure of one or several treatment lines. We excluded patients with clinically atypical BP, as per Vaillant's criteria. The criteria for clinical response to omalizumab were defined according to the 2012 international consensus conference. Anti-BP180-NC16A IgE enzyme-linked immunosorbent assay was performed on sera collected before initiating omalizumab, when available. RESULTS: Between 2014 and 2021, 100 patients treated in 18 expert departments were included. Median age at diagnosis was 77 years (range 20-98). Complete remission (CR) was achieved in 77% of patients, and partial remission in an additional 9%. CR was maintained 'off therapy' in 11.7%, 'on minimal therapy' in 57.1%, and 'on non-minimal therapy' in 31.2%. Median time to CR was 3 months (range 2.2-24.5). Relapse rate was 14%, with a median follow-up time of 12 months (range 6-73). Adverse events occurred in four patients. CR was more frequently observed in patients with an increased serum baseline level of anti-BP180-NC16A IgE (75% vs. 41%; P = 0.011). Conversely, urticarial lesions, blood total IgE concentration or eosinophil count were not predictive of CR. Patients with an omalizumab dosage > 300 mg every 4 weeks showed a similar final outcome to those with a dosage ≤ 300 mg every 4 weeks, but control of disease activity [median 10 days (range 5-30) vs. 15 days (range 10-60); P < 0.001] and CR [median 2.4 months (range 2.2-8.2) vs. 3.9 months (range 2.3-24.5); P < 0.001] were achieved significantly faster. CONCLUSIONS: We report the largest series to date of BP treated by omalizumab and confirm its effectiveness and safety in this indication. Serum baseline level of anti-BP180-NC16A IgE may predict response to treatment.

High-dimensional immune profiles correlate with phenotypes of peanut allergy during food-allergic reactions.

BACKGROUND: Food challenges carry a burden of safety, effort and resources. Clinical reactivity and presentation, such as thresholds and symptoms, are considered challenging to predict ex vivo. AIMS: To identify changes of peripheral immune signatures during oral food challenges (OFC) that correlate with the clinical outcome in patients with peanut allergy (PA). METHODS: Children with a positive (OFC+ , n = 16) or a negative (OFC- , n = 10) OFC-outcome were included (controls, n = 7). Single-cell mass cytometry/unsupervised analysis allowed unbiased immunophenotyping during OFC. RESULTS: Peripheral immune profiles correlated with OFC outcome. OFC+ -profiles revealed mainly decreased Th2 cells, memory Treg and activated NK cells, which had an increased homing marker expression signifying immune cell migration into effector tissues along with symptom onset. OFC- -profiles had also signs of ongoing inflammation, but with a signature of a controlled response, lacking homing marker expression and featuring a concomitant increase of Th2-shifted CD4+ T cells and Treg cells. Low versus high threshold reactivity-groups had differential frequencies of intermediate monocytes and myeloid dendritic cells at baseline. Low threshold was associated with increased CD8+ T cells and reduced memory cells (central memory [CM] CD4+ [Th2] T cells, CM CD8+ T cells, Treg). Immune signatures also discriminated patients with preferential skin versus gastrointestinal symptoms, whereby skin signs correlated with increased expression of CCR4, a molecule enabling skin trafficking, on various immune cell types. CONCLUSION: We showed that peripheral immune signatures reflected dynamics of clinical outcome during OFC with peanut. Those immune alterations hold promise as a basis for predictive OFC biomarker discovery to monitor disease outcome and therapy of PA.

Treatment of dissecting cellulitis of the scalp with tumour necrosis factor inhibitors: a retrospective multicentre study.

Although retinoids are considered as the most effective treatment, management of dissecting cellulitis of the scalp (DCS) is often challenging. A multicentre retrospective study was conducted to evaluate the efficacy of anti-tumour necrosis factor (TNF) agents in treating DCS after failure of other conventional treatments. Twenty-six patients were included. After a mean treatment duration of 19 months (SD 21), the median Physician's Global Assessment score decreased from 3 to 1. The median number of inflammatory nodules and abscesses decreased from 7 to 0.5 and from 1 to 0, respectively. The median Dermatology Life Quality Index and numerical rating scale score for pain severity decreased from 10 to 8 and 6 to 1, respectively. The median treatment satisfaction was 7 out of 10 on the Patient Satisfaction Index. This study confirms the efficacy of anti-TNF agents in treating patients with DCS that is resistant to conventional therapies.

Anti-BP180 IgG antibody ELISA values correlate with adverse pregnancy outcomes in pemphigoid gestationis.

BACKGROUND: Adverse pregnancy outcomes (APO) occur in 35% of patients with pemphigoid gestationis (PG). No biological predictor of APO has been established yet. OBJECTIVES: To assess a potential relationship between the occurrence of APO and the serum value of anti-BP180 antibodies at the time of PG diagnosis. METHODS: Multicentre retrospective study conducted from January 2009 to December 2019 in 35 secondary and tertiary care centres. INCLUSION CRITERIA: (i) diagnosis of PG according to clinical, histological and immunological criteria, (ii) ELISA measurement of anti-BP180 IgG antibodies determined at the time of PG diagnosis with the same commercial kit and (iii) obstetrical data available. RESULTS: Of the 95 patients with PG included, 42 had one or more APO, which mainly corresponded to preterm birth (n = 26), intrauterine growth restriction (IUGR) (n = 18) and small weight for gestational age at birth (n = 16). From a ROC curve, we identified a threshold of 150 IU ELISA value as the most discriminating to differentiate between patients with or without IUGR, with 78% sensitivity, 55% specificity, 30% positive and 91% negative predictive value. The threshold >150 IU was confirmed using a cross-validation based on bootstrap resampling, which showed that the median threshold was 159 IU. Upon adjusting for oral corticosteroid intake and main clinical predictors of APO, an ELISA value of >150 IU was associated with the occurrence of IUGR (OR = 5.11; 95% CI: 1.48-22.30; p = 0.016) but not with any other APO. The combination of blisters and ELISA values higher than 150 IU led to a 2.4-fold higher risk of all-cause APO (OR: 10.90; 95% CI: 2.33-82.3) relative to patients with blisters but lower values of anti-BP180 antibodies (OR of 4.54; 95% CI 0.92-34.2). CONCLUSION: These findings suggest that anti-BP180 antibody ELISA value in combination with clinical markers is helpful in managing the risk of APO, in particular IUGR, in patients with PG.

Real-life impact of immunologic tests to predict relapse after treatment cessation in patients with bullous pemphigoid: A French multicenter retrospective study.

BACKGROUND: A high level of anti-BP180 antibodies on enzyme-linked immunosorbent assay and a persistent positive direct immunofluorescence at the end of treatment (immunologic tests, [ITs]) are predictors of relapse after treatment cessation (TC) in patients with bullous pemphigoid. OBJECTIVE: To evaluate the real-life impact of the immunologic-based decision of TC on the 3- and 6-month relapse rates after TC in bullous pemphigoid. METHODS: Retrospective multicentric study included patients followed almost 6 months after TC. Patients were classified according to whether the TC decision was in accordance with the results of ITs performed during the 3 months before TC, despite the results of ITs or without ITs performed. RESULTS: We included 238 patients. Three months after TC, 36 patients showed relapse: 14 of 95 patients with TC in accordance with IT results (14.7%); 5 of 21 with TC despite ITs (23.8%); and 17 of 122 with TC without ITs (13.9%; P = .5). Six months after TC, the relapse rate was 18.9%, 28.6%, and 18.9% (P = .56), respectively, in the 3 groups. LIMITATIONS: The retrospective design and the limited follow up. CONCLUSION: In real-life practice, in bullous pemphigoid, the 3- and 6-month relapse rates were not significantly reduced with TC decision based on results of ITs as compared with a classic clinical-based decision.

Effect of anaesthesia on cell-mediated immunity in dogs undergoing mastectomy for mammary cancer.

OBJECTIVE: To investigate if anaesthesia for canine cancer mastectomy further influences host cell-mediated immunity (CMI) promoting cancer progression. STUDY DESIGN: A randomized, controlled, blinded clinical study. ANIMALS: A total of 20 bitches with malignant mammary tumours of clinical stage II or III undergoing the same type of mastectomy (regional mastectomy). METHODS: Dogs were randomly allocated to one of two anaesthetic groups (10 per group). The anaesthetic protocol of group A used minimally immunosuppressive drugs (tramadol, robenacoxib, propofol), whereas that of group B (control) used more immunosuppressive drugs (morphine, fentanyl, thiopental, isoflurane). For each animal, measurements of white blood cells (WBCs), neutrophils and lymphocytes, and flow cytometric assessment of T cells (CD3+), helper T cells (CD4+), cytotoxic T cells (CD8+) and CD5low+ T cells were performed prior to anaesthesia (day 0) and on days 3 and 10 postsurgery. Data were analysed using a General Linear Model for repeated measures and presented as mean ± standard deviation, p ≤ 0.05. RESULTS: In all animals, on day 3, WBCs and neutrophils were significantly increased (p < 0.0005), while flow cytometry revealed significantly decreased relative percentages of T cells (CD3+) (p = 0.003) and their subpopulations CD4+ (p = 0.006), CD8+ (p = 0.029) and CD5low+ (p = 0.031). Specifically, on day 3, the cytotoxic T cells (CD8+) were significantly decreased (p = 0.05) only in group B, whereas the CD4+ (p = 0.006) and CD5low+ (p = 0.008) T cells in group A. The only significant difference between groups was found preoperatively in the CD4+/CD8+ ratio, which was higher in group A (p = 0.006). CONCLUSIONS AND CLINICAL RELEVANCE: In dogs with mammary cancer undergoing regional mastectomy, a significant decrease in components of CMI was observed on day 3 postsurgery in both anaesthetic groups. Some indication, however, for better preserved cellular immunity by less immunosuppressive anaesthetic/analgesic drugs was detected, rendering their use advisable.

Data integration and visualization techniques for post-cytometric analysis of complex datasets.

The increasing number of measurable markers and the need to integrate flow cytometry datasets with data generated by other high throughput technologies, require the use of innovative tools, easy enough to be used by people with diverse levels of informatics skills. Flow cytometry analysis software has principally been designed for single sample analysis and it does not cover all the successive analysis steps such as integration with metadata and complex visualization. Here, we illustrated the use of data integration and visualization tools generally used in the business sector to analyze datasets generated by mass and flow cytometry. We selected a study that used mass cytometry to characterize immune cells in lung adenocarcinoma and a second study that used flow cytometry to characterize the expression signature of CD markers on human immune cells. These two examples showed the effectiveness of these tools in the analysis of cytometry data and the possibility to expand their use in any field of biology.

How to assess patient satisfaction regarding physician interaction: A systematic review.

Patient satisfaction is an important health care quality indicator. This is particularly relevant in chronic diseases, such as, many dermatological diseases. The purpose of the current systematic review was to assess the validated tools measuring patient satisfaction with physician interaction. We performed a systematic review search in Pubmed, Cochrane Library, and EMBASE. The psychometric properties of the instruments and the domains explored were assessed. Overall, 2229 articles were extracted from the literature search. Of these, 146 articles were eligible for inclusion, 55 were included, and 22 scores were selected. A total of 13 instruments reported cross-cultural validation and the EUROPEP score highlighted the most diverse cross-cultural validation involving 11 different countries. All scores were assessed for content validity, construct validity, factor analysis, reliability, and responsiveness to change. The extent of the validation varied between scores with a few assessing practicability. The following domains were explored: listening skills, empathy, caring/compassion, confidentiality, honesty, behavior, competency/technical skills, satisfaction with the information provided, time given, availability, the environment, trust in the physician, ability to comply with the recommendations, and readiness to recommend the physician to other patients. We identified a total of 22 validated instruments. The major gaps in the validation process appear to be the practicability of the scores and the cross-cultural validation. Major domains evaluated by the scores are communication skills that can be improved by specific training. There is a need to improve evaluation of the quality of the patient-physician relationship in dermatology using validated instruments.

Diagnostic and prognostic value of peripheral blood leucocyte ratios in sick cats.

The objective of this study was to assess the diagnostic and prognostic utility of feline neutrophil-to-lymphocyte (NLR) and lymphocyte-to-monocyte ratios (LMR) in a variety of underlying diseases. Five-year medical records from cats presenting to the internal medicine unit of a veterinary teaching hospital were retrospectively reviewed. Cats were considered for inclusion based on complete medical records. ADVIA 120 was used for the complete blood counts; the NLR and LMR were calculated by dividing the absolute numbers of the respective leucocytes. Two hundred and nineteen sick and 20 healthy cats were included in the study. The median NLR and LMR were significantly (P < 0.05) elevated and decreased, respectively, in cats with infectious, neoplastic and chronic kidney diseases compared to controls. Additionally, cats with neoplasia had significantly higher median NLR compared to cats with urinary tract and gastrointestinal diseases. Non-survivors had significantly higher NLR and lower LMR compared to survivors. Both ratios had suboptimal prognostic performance for the outcome of sick cats (NLR sensitivity: 37.9%, specificity: 86.4%; LMR sensitivity: 69.0%, specificity: 61.0%). Many different disease categories were associated with increased NLR and decreased LMR compared to controls, but the overall prognostic performance of the two leucocyte ratios was suboptimal.

What causes hidradenitis suppurativa ?-15 years after.

The 14 authors of the first review article on hidradenitis suppurativa (HS) pathogenesis published 2008 in EXPERIMENTAL DERMATOLOGY cumulating from the 1st International Hidradenitis Suppurativa Research Symposium held March 30-April 2, 2006 in Dessau, Germany with 33 participants were prophetic when they wrote "Hopefully, this heralds a welcome new tradition: to get to the molecular heart of HS pathogenesis, which can only be achieved by a renaissance of solid basic HS research, as the key to developing more effective HS therapy." (Kurzen et al. What causes hidradenitis suppurativa? Exp Dermatol 2008;17:455). Fifteen years later, there is no doubt that the desired renaissance of solid basic HS research is progressing with rapid steps and that HS has developed deep roots among inflammatory diseases in Dermatology and beyond, recognized as "the only inflammatory skin disease than can be healed". This anniversary article of 43 research-performing authors from all around the globe in the official journal of the European Hidradenitis Suppurativa Foundation e.V. (EHSF e.V.) and the Hidradenitis Suppurativa Foundation, Inc (HSF USA) summarizes the evidence of the intense HS clinical and experimental research during the last 15 years in all aspects of the disease and provides information of the developments to come in the near future.

Compounded topical preparations in plaque psoriasis: Still a place for it in 2018?

Compounded topical preparations (CTP) were used to treat psoriasis until the last century and have disappeared from guidelines. The present authors report two severe psoriasis patients who were treated with CTP. A man had psoriasis with a PASI of 23 and a body surface area (BSA) of 43%. He had been using daily for several weeks a CTP including minoxidil, clobetasol propionate and hydroxyprogesterone formulated in an alcohol based vehicle. A woman suffered from psoriasis with an annular inflammatory pattern and a central healing. The PASI was 20 and the BSA was 30%. She had been using a CTP daily for 4 months including resorcinol, salicylic acid, 0.05% tretinoin cream, bethamethasone dipropionate cream. Until the 1970s, the dermatological textbooks recommended to treat severe psoriasis with CTP. Nowadays, CTP are considered outdated because of the large therapeutic armamentarium. The stability and benefit risks of the CTP used here were not documented. The use of CTP in psoriasis should be regulated and must be evidence based. Strict protocol and stability evaluation for preparations must be confirmed prior to compounding.

Canine and feline dirofilariosis in a highly enzootic area: first report of feline dirofilariosis in Greece.

Dirofilaria immitis (heartworm) is enzootic in many areas of the world and quite prevalent in southern European countries. Although dogs are the main host of the parasite, cats may also be infected, and the prevalence of feline dirofilariosis is associated with the respective prevalence of canine infection in any given area. The aim of the present study was to investigate the proportion of D. immitis infection among dogs and cats that were not under any kind of prophylactic treatment and were living in a heartworm enzootic area. In total, 180 stray animals (148 dogs and 32 cats) living in a shelter in Northern Greece were examined for heartworm infection by the Knott's test and serology (antigen and in cats also antibody detection), and additionally echocardiography in the infected cats. Thirty-seven (25%, CI 18.7-32.5%) of the dogs and 3 (9.4%, CI 3.2-24.2%) of cats were found to be positive, by at least one of the tests applied. In 2 of the infected cats, the parasites were also detected by echocardiography. One of the positive cats died suddenly 1 year after diagnosis and at necropsy two decomposing D. immitis were found in the right ventricle and pulmonary artery. This is the first report of confirmed feline dirofilariosis in Greece. The detected proportion of infection in cats was 38% of the respective canine infection in the examined shelter. The results of the present study underline the high risk of infection of cats living in enzootic areas and the imperative character of preventive measures in such conditions.

Serratus anterior plane block for minimal invasive heart surgery.

BACKGROUND: Minimal invasive heart surgery (MIHS) presents several benefits, but provides intense and prolonged post-operative pain. Our objective was to compare efficacy of serratus anterior plane block (SAPB) with continuous wound infiltration (CWI) for management of post-operative pain following MIHS. METHODS: It's retrospective, monocentric study between November 2016 to April 2017. The study was performed at the University hospital of Dijon, Burgundy, France. All patients scheduled for MIHS was included. Data was collected retrospectively. During this period, 20 patients had SAPB and 26 had CWI. SAPB was performed before extubation with a single injection of 0.5 mg/kg of ropivacaïne (5 mg/ml). In the CWI group, catheter was inserted in the subcutaneous space by the surgeon at the end of the procedure. A 10 ml bolus of ropivacaïne (7.5 mg/mL) was followed by a continuous infusion (2 mg/ml) between 7 and 12 ml/h for 48 h. Morphine consumption and visual analog score (VAS) were recorded for 48 h. Length of stay in intensive care unit and hospital was also collected. RESULTS: Morphine consumption and VAS score were significantly lower in SAPB group (p < 0.01). Length of stay in intensive care and hospital was significantly was decreased in SAPB group. CONCLUSION: SAPB appears effective in reducing postoperative MIHS pain.

Potential Dissociative Glucocorticoid Receptor Activity for Protopanaxadiol and Protopanaxatriol.

Glucocorticoids are steroid hormones that regulate inflammation, growth, metabolism, and apoptosis via their cognate receptor, the glucocorticoid receptor (GR). GR, acting mainly as a transcription factor, activates or represses the expression of a large number of target genes, among them, many genes of anti-inflammatory and pro-inflammatory molecules, respectively. Transrepression activity of glucocorticoids also accounts for their anti-inflammatory activity, rendering them the most widely prescribed drug in medicine. However, chronic and high-dose use of glucocorticoids is accompanied with many undesirable side effects, attributed predominantly to GR transactivation activity. Thus, there is a high need for selective GR agonist, capable of dissociating transrepression from transactivation activity. Protopanaxadiol and protopanaxatriol are triterpenoids that share structural and functional similarities with glucocorticoids. The molecular mechanism of their actions is unclear. In this study applying induced-fit docking analysis, luciferase assay, immunofluorescence, and Western blot analysis, we showed that protopanaxadiol and more effectively protopanaxatriol are capable of binding to GR to activate its nuclear translocation, and to suppress the nuclear factor-kappa beta activity in GR-positive HeLa and HEK293 cells, but not in GR-low level COS-7 cells. Interestingly, no transactivation activity was observed, whereas suppression of the dexamethasone-induced transactivation of GR and induction of apoptosis in HeLa and HepG2 cells were observed. Thus, our results indicate that protopanaxadiol and protopanaxatriol could be considered as potent and selective GR agonist.

Fast-Track Recovery Program After Major Liver Resection: A Randomized Prospective Study.

The objective of this study was to compare fast-track (FT) recovery protocol with the conventional one in patients treated with major liver resection by evaluating perioperative morbidity, length of hospitalization, and readmission rate. Sixty-two patients suffering from malignant liver tumors were surgically treated from May 2012 to April 2014. After randomization, they were prospectively divided into two groups: Group A patients (n = 32) followed FT recovery protocol and Group B patients (n = 30) were treated with the conventional (CON) protocol. Postoperative morbidity, readmission rate, and median hospital stay in the two groups were studied. Fast-track protocol was associated with a decreased complication (25%, p = .002), whereas the risk of postoperative morbidity was 2.4 times higher in patients treated with the CON protocol (60%, p = .002). Readmission rate was not significantly different between the two groups (6.25%, p = .35). Age (p = .382) and body mass index (p = .818) were not a suspending factor for following the FT protocol. Overall length of stay (postoperative days) in the FT group was (mean ± SD) 5.75 ± .5 and in the CON group was 13.5 ± 6.7 (p < .001). Fast-track recovery protocol seems to be safe and particularly efficient in patients undergoing major liver resections.