Modulation of Leukocytes of the Innate Arm of the Immune System as a Potential Approach to Prevent the Onset and Progression of Type 1 Diabetes

Type 1 diabetes (T1D) is characterized by insulin deficiency resulting from the selective destruction of pancreatic β-cells by self-reactive T cells. Recent evidence demonstrates that innate immune responses substantially contribute to the pathogenesis of T1D, as they represent a first line of response to danger/damage signals. Here we discuss evidence on how, in a relapsing-remitting pattern, pancreas remodeling, diet, microbiota, gut permeability, and viral/bacterial infections induce the accumulation of leukocytes of the innate arm of the immune system throughout the pancreas. The subsequent acquisition and presentation of endocrine and exocrine antigens to the adaptive arm of the immune system results in a chronic progression of pancreatic damage. This process provides for the generation of self-reactive T-cell responses; however, the relative weight that genetic and environmental factors have on the etiopathogenesis of T1D is endotype imprinted and patient specific. With this Perspectives in Diabetes, our goal is to encourage the scientific community to rethink mechanisms underlying T1D pathogenesis and to consider therapeutic approaches that focus on these processes in intervention trials within new-onset disease as well as in efforts seeking the disorder’s prevention in individuals at high risk.     

Surgeon experience contributes to improved outcomes in pancreatoduodenectomies at high risk for fistula development

BackgroundPancreatoduodenectomies at high risk for clinically relevant pancreatic fistula are uncommon, yet intimidating, situations. In such scenarios, the impact of individual surgeon experience on outcomes is poorly understood.MethodsThe fistula risk score was applied to identify high-risk patients (fistula risk score 7–10) from 7,706 pancreatoduodenectomies performed at 18 international institutions (2003–2020). For each case, surgeon pancreatoduodenectomy career volume and years of practice were linked to intraoperative fistula mitigation strategy adoption and outcomes. Consequently, best operative approaches for clinically relevant pancreatic fistula prevention and best performer profiles were identified through multivariable analysis models.ResultsEight hundred and thirty high-risk pancreatoduodenectomies, performed by 64 surgeons, displayed an overall clinically relevant pancreatic fistula rate of 33.7%. Clinically relevant pancreatic fistula rates decreased with escalating surgeon career pancreatoduodenectomy (–49.7%) and career length (–41.2%; both P < .001), as did transfusion and reoperation rates, postoperative morbidity index, and duration of stay. Great experience (≥400 pancreatoduodenectomies performed or ≥21-year-long career) was a significant predictor of clinically relevant pancreatic fistula prevention (odds ratio 0.52, 95% confidence interval 0.35–0.76) and was more often associated with pancreatojejunostomy reconstruction and prophylactic octreotide omission, which were both independently associated with clinically relevant pancreatic fistula reduction. A risk-adjusted performance analysis also correlated with experience. Moreover, minimizing blood loss (≤400 mL) significantly contributed to clinically relevant pancreatic fistula prevention (odds ratio 0.40, 95% confidence interval 0.22–0.74).ConclusionSurgeon experience is a key contributor to achieve better outcomes after high-risk pancreatoduodenectomy. Surgeons can improve their performance in these challenging situations by employing pancreatojejunostomy reconstruction, omitting prophylactic octreotide, and minimizing blood loss.     

The utility of in-bore multiparametric magnetic resonance-guided biopsy in men with negative multiparametric magnetic resonance-ultrasound software-based fusion targeted biopsy

ObjectivesTo evaluate the utility of in-bore multiparametric magnetic resonance-guided biopsy of the prostate (IB) in patients with visible lesion/s and previous negative software-based multiparametric magnetic resonance imaging/ultrasonography fusion-targeted biopsy of the prostate (FTB).Patients and methodsWe retrospectively analysed prospectively maintained database including consecutive men undergoing IB from March 2013 to October 2017 in 2 European centres expert in this procedure. We selected men with the following criteria: No previous treatment for prostate cancer (CaP), multiparametric magnetic resonance imaging (mpMRI) lesion(s) PIRADS score ≥ 3, FTB showing no clinically significant cancer (csCaP), and subsequent IB. Patient's characteristics, mpMRI findings, biopsy technique, and histopathological results were extracted. The primary outcome was to determine the detection rate of csCaP, defined as any Gleason pattern ≥ 4. A multivariable analysis was performed to identify predictors of positive findings at IB.ResultsFifty-three men were included. Median age was 68 years (interquartile range [IQR] 64–68), median Prostate-Specific Antigen (PSA) was 7.6 ng/ml (IQR 5.2–10.9), and median prostate volume was 59 ml (IQR 44–84). Fifty-six lesions with PIRADS score 3 in 9 cases (16%), 4 in 30 cases (54%), and 5 in 17 cases (30%) were detected. FTB was performed in all cases using a transrectal approach with 3 different platforms (Toshiba, Koelis, and Artemis). Median time between FTB and IB was 3 months (IQR 1–7). A median of 2 cores per lesion were collected with IB (IQR 2–3). No cancer, clinically insignificant and clinically significant cancer were found in 33 (59%), 9 (16%), and 14 (25%) targeted lesions, respectively. Median maximum cancer core length and maximum positive percentage were 9 mm (3–13) and 55% (21%–80%). The only predictor of csCaP on IB was prostate volume (P = 0.026) with an ideal cut-off at 70 ml.ConclusionOne in 4 patients with previous negative FTB, IB was able to detect csCaP. According to this study, IB would be of particularly useful in patients with large glands.     

Occupational contact dermatitis in a gender perspective: North East Italian data 1996-2016

Background:Occupational contact dermatitis (OCD) ranks high among occupational diseases in Europe, but little is known as regards OCD and jobs in a gender perspective.Objectives:To evaluate sex prevalence of OCD according to occupational sectors and agents involved. 27381 patients (1996–2016) with suspected irritant/allergic contact dermatitis (ICD-ACD) were evaluated in North-Eastern Italy. Each patient underwent: a standardized questionnaire, a dermatologist/occupational physician evaluation and a patch test.Results:Females were younger at diagnosis (35.2 ± 11.6 years vs 37.7 ± 12.6 in males, p< 0.001) and had a lower ICD prevalence (OR 0.58, C.I. 95% 0.51 - 0.66, p < 0.001). Job categories most involved differed between sexes, with highest rank for healthcare professionals in females and machinery mechanics and filters for males. In females ACD percentage was higher in all job categories.Conclusions:OCD characteristics differ between sexes, according to intrinsic and extrinsic factors. Use of personal care products, housekeeping products and outdoor work activities may account for different sensitization profiles.     

Excision of the aortic wall in the surgical treatment of acute type-A aortic dissection

Between March 1986 and September 1988, 38 patients underwent extended aortic resection (aortic valve, ascending aorta, and arch) for acute type-A aortic dissection with aortic valve insufficiency; deep hypothermia and circulatory arrest were used. All patients were operated on within 17 hours of the onset of symptoms. In the first 24 patients, operation was performed by the "inclusion technique." In the last 14 patients, the "excision technique" was used: the ascending aorta and arch was excised, and the aorta was transected at the beginning of the descending thoracic tract. Excision and transection were considered essential to prevent back flow from the false lumen, which is the main source of bleeding, and to allow all anastomoses to be constructed beyond the limits of dissection. The only anastomosis to the dissected aorta was at the distal end of the graft. One of the 14 patients died (7.1%). One patient was reopened for bleeding: blood was issuing from the attachment of the carotid trunks, and the defect was repaired by interposing a bifurcated Dacron graft between the arch graft and the carotid arteries. Extended aortic excision meets the principle of either eliminating as far as possible the diseased aorta or controlling intraoperative and postoperative bleeding. An operation of great magnitude can be considered a life-saving procedure when compared with the high risk of acute type-A aortic dissection.     

Anastomosis

Esophageal anastomosis is still associated with a high rate of complications even though they have decreased considerably in recent years. Anastomotic leaks are more frequent in the neck than in the chest, and related mortality rate is not different. The leakage incidence does not depend on suture materials or on technical modalities used to perform the anastomosis. In fact, there is no difference between the leakage rate when comparing manual and mechanical anastomoses. The leak incidence after both mechanical and manual anastomoses is much higher in collective reviews than in reports coming from leading centers. Frequent esophageal surgeons can learn from their previous experience and therefore avoid technical errors, whereas casual esophageal surgeons do not have this opportunity. Performing an esophageal anastomosis is a technical matter, and suture healing is independent of the patient's biologic situation. Anastomotic fibrotic stricutures are frequent after both manual and mechanical anastomoses, and most can be avoided by meticulous suturing technique.

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Resumen La anastomosis esofágica todavía se asocia con una elevada incidencia de complicaciones, a pesar de que éstas han descendido en forma considerable en los últimos años. Las fugas anastomóticas son más frecuentes en el cuello que en el tórax y las tasas de mortalidad no son diferentes. La rata de fuga anastomótica no depende de los materiales de sutura o de las modalidades técnicas que se utilicen para realizar la anastomosis. De hecho no hay diferencia en cuanto a la rata de fugas entre las anastomosis manuales y las mecánicas. La incidencia de fuga, tanto en las manuales como en las mecánicas, es bastante más alta en las revisiones colectivas que en los reportes emanados de los centros médicos de mayor importancia. Los cirujanos especialistas en esófago tienen la posibilidad de aprender de sus experiencias previas y con ello evitar los errores técnicos, en tanto que aquellos cirujanos ocasionales no la poseen. La realización de una anastomosis esofágica es un asunto técnico y la cicatrización de la sutura es independiente de la condición biológica del paciente. Las estrecheces fibróticas de las anastomosis son frecuentes luego de las anastomosis manuales, al igual que luego de las anastomosis mecánicas y la mayoría puede ser evitada mediante una técnica meticulosa.

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Résumé Le taux de complications des anastomoses oesophagiennes, même s'il y en a moins ces dernières années, reste toujours élevé. La fréquence de fistules est plus grande quand l'anastomose est faite au cou par rapport au thorax, mais la mortalité n'en est pas très différente. L'incidence de fistules ne dépend ni du matériau de suture ni des modalités d'anastomoses utilisées. Il n'y a aucune différence lorsque les anastomoses manuelles sont comparées aux anastomoses méchaniques: L'incidence des fistules, que ce soit à la main ou à la machine est plus élevée dans les séries collectives par rapport à celle des centres spécialisés. Les chirurgiens qui font des anastomoses de façon régulière ont la possibilité de profiter de leur expérience et ainsi d'éviter les erreurs techniques, alors que le chirurgien occasionnel de l'oesophage n'a pas cette possibilité. L'anastomose oesophagienne est techniquement difficile et la cicatrisation est indépendante de l'état clinique et biologique du patient. Les sténoses fibreuses sont aussi fréquentes après les anastomoses manuelles qu'après les anastomoses méchaniques, mais la plupart peuvent être évitées par une technique méticuleuse.

     

Stress, attachment and skin diseases: a case-control study

Objectives In this case-control study we tested the hypothesis of an association between some psychosomatic skin diseases, attachment style and stress. Patients and methods A total of 177 cases and 194 controls seen between November 1992 and November 1993 at the Istituto Dermopatico dell'lmmacolata (IDD) in Rome, were enrolled into the study. Cases were outpatients with first diagnosis of hyperidrosis, chronic urticaria, generalized pruritus or alopecia areata. Controls were outpatients seen in the same period of time with first diagnosis of pigmenled nevi, keratosis or mycosis. The presence and weight of life stress events were assessed by u standard precoded questionnaire based on the Schedule of Recent Experiences (SRE) and on the Life Experiences Survey (LES). The attachment style was assessed by a modified version of the Shaver and Hazan questionnaire about feelings in a love relationship. We calculated 3 scores for each individual and classified study subjects in 2 groups: 1) "free" (= secure attachment); 2) "not free" (not secure attachment: anxious-ambivalent or avoidant). Questionnaires were self-administered in the presence of a trained psychologist. Adjusted odds ratios (OR) were calculated using a multiple logistic function. Results No association was found between the different stress scores and the skin diseases considered. The crude odds ratio for life stress events in the previous year was 1.4 (95% CI 0.8–2.7). After multiple adjustment for age, sex, marital status and education, the estimated OR was 1.6 (95% CI 0.8–3.0). One significant association emerged between the adult attachment style defined as “not free” and psychosomatic skin diseases: the adjusted OR was 4.0 (95% CI 1.4–12).     

Early-onset encephalomyopathy associated with tissue-specific mitochondrial DNA depletion: A morphological,biochemical and molecular-genetic study

A male infant, born from consanguineous parents, suffered from birth with a progressive neuromuscular disorder characterized by psychomotor delay, hypotonia, muscle weakness and wasting, deep-tendon areflexia and spastic posture. High levels of lactic acid in blood and cerebrospinal fluid suggested a mitochondrial respiratory chain defect. Muscle biopsy revealed raggedred and cytochromec oxidase-negative fibres, lipid accumulation and dystrophic changes. Multiple defects of respiratory complexes were detected in muscle homogenate, but cultured fibroblasts, myoblasts and myotubes were normal. Southern blot analysis showed markedly reduced levels of mitochondrial DNA (mtDNA) in muscle, while lymphocytes, fibroblasts and muscle precursor cells were normal. Neither depletion of mtDNA nor abnormalities of the respiratory complexes were observed in innervated muscle fibres cultured for as long as 4 months. No mutations were observed in two candidate nuclear genes,mtTFA andmtSSB, retro-transcribed, amplified and sequenced from the proband's mRNA. Sequence analysis of the mtDNA D-loop and of the origin of replication of the mtDNA light strand failed to identify potentially pathogenic mutations of these replicative elements in the proband's muscle mtDNA. Our findings indicate that mtDNA depletion is due to a nuclear encoded gene and suggest that the abnormality underlying defective mtDNA propagation must occur after muscle differentiation in vivo.