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In contrast to natural antibodies that rely mainly on the heavy chain to establish contacts with their cognate antigen, we have developed a bispecific antibody format in which the light chain (LC) drives antigen binding and specificity. To better understand epitope-paratope interactions in this context, we determined the X-ray crystallographic structures of an antigen binding fragment (Fab) in complex with human CD47 and another Fab in complex with human PD-L1. These Fabs contain a κ-LC and a λ-LC, respectively, which are paired with an identical heavy chain (HC). The structural analysis of these complexes revealed the dominant contribution of the LCs to antigen binding, but also that the common HC provides some contacts in both CD47 and PD-L1 Fab complexes. The anti-CD47 Fab was affinity optimized by diversifying complementary-determining regions of the LC followed by phage display selections. Using homology modeling, the contributions of the amino acid modification to the affinity increase were analyzed. Our results demonstrate that, despite a less prominent role in natural antibodies, the LC can mediate high affinity binding to different antigens and neutralize their biological function. Importantly, Fabs containing a common variable heavy (VH) domain enable the generation of bispecific antibodies retaining a truly native structure, maximizing their therapeutic potential.

Abstract Background T-cell retargeting to eliminate CEACAM5-expressing cancer cells via CEACAM5xCD3 bispecific antibodies (BsAbs) showed limited clinical activity so far, mostly due to insufficient T-cell activation, dose-limiting toxicities, and formation of anti-drug antibodies (ADA). Methods We present here the generation and preclinical development of NILK-2301, a BsAb composed of a common heavy chain and two different light chains, one kappa and one lambda, determining specificity (so-called κλ body format). Results NILK-2301 binds CD3ɛ on T-cells with its lambda light chain arm with an affinity of ≈100 nM, and the CEACAM5 A2 domain on tumor cells by its kappa light chain arm with an affinity of ≈5 nM. FcγR-binding is abrogated by the “LALAPA” mutation (Leu234Ala, Leu235Ala, Pro329Ala). NILK-2301 induced T-cell activation, proliferation, cytokine release, and T-cell dependent cellular cytotoxicity of CEACAM5-positive tumor cell lines (5/5 colorectal, 2/2 gastric, 2/2 lung), e.g., SK-CO-1 (E max = 89%), MKN-45 (E max = 84%), and H2122 (E max = 97%), with EC50 ranging from 0.02 to 0.14 nM. NILK-2301 binds neither to CEACAM5-negative or primary colon epithelial cells nor to other CEACAM family members. NILK-2301 alone or in combination with checkpoint inhibition showed activity in organotypic tumor tissue slices and colorectal cancer organoid models. In vivo, NILK-2301 at 10 mg/kg significantly delayed tumor progression in colon- and a pancreatic adenocarcinoma model. Single-dose pharmacokinetics (PK) and tolerability in cynomolgus monkeys at 0.5 or 10 mg/kg intravenously or 20 mg subcutaneously showed dose-proportional PK, bioavailability ≈100%, and a projected half-life in humans of 13.1 days. NILK-2301 was well-tolerated. Data were confirmed in human FcRn TG32 mice. Conclusions In summary, NILK-2301 combines promising preclinical activity and safety with lower probability of ADA-generation due to its format compared to other molecules and is scheduled to enter clinical testing at the end of 2023.

Abstract Background Parkinson’s disease (PD) is a common neurodegenerative disease. No disease-modifying treatment is available, and therapy is symptomatic. The histopathologic hallmark is the loss of dopaminergic neurons and accumulation of α-synuclein (α-syn) in surviving neurons, but the underlying pathophysiology is unclear. Inflammatory mechanisms seem to play a prominent role, with an imbalance of immune functions and neurotoxicity caused by reactive oxygen species (ROS). Involvement of peripheral adaptive immunity, with an imbalance in T cell subpopulations and in the expression of transcriptional factors in CD4+ T cells, has also been reported. Although clinical presentation is defined by motor symptoms, patients also report non-motor symptoms, often before the onset of a clinically established disease. Etiopathogenesis of PD is unknown, but an initial aggregation of α-syn in the gut, with subsequent propagation along the vagus nerve to the brain has been hypothesised. Interestingly, in an α-syn overexpressing murine model, the absence of gut microbiota prevented both microglia activation and motor impairment, thus pointing to a fundamental role of microbiota in the development of PD. Magistrelli et al. showed that in peripheral blood mononuclear cells of PD patients, probiotics modulate the in vitro production of cytokines toward an anti-inflammatory profile and reduce the production of ROS. Methods This is a pilot randomised placebo-controlled clinical trial protocol for a 12-week treatment with probiotics. At least 80 patients affected by PD will be recruited and randomly allocated to either the treatment or placebo group in a 1:1 ratio. General inclusion criteria will be the onset of PD 2 to 5 years before the trial and absence of autoimmune comorbidities or immunomodulating therapy. Our primary endpoint is the assessment of changes in extracellular cytokine levels (Interferon (IFN)-γ, tumour necrosis factor (TNF)-α, interleukin (IL)-4, and IL-10) and ROS production. Secondary outcomes include changes in lymphocyte subpopulations and transcriptional factors mRNA levels. Discussion This study is designed to highlight the potential beneficial role of probiotics administration on peripheral immunity through the modulation of gut microbiota. Explorative outcomes will be evaluated to assess variations in motor and non-motor symptoms and the possible correlation with probiotics administration. Trial registration ClinicalTrials.gov ID NCT05173701. Registered 08 November 2021

BackgroundTo date, there are no large studies delineating the clinical correlates of “pure” essential tremor (ET) according to its new definition.MethodsFrom the ITAlian tremor Network (TITAN) database, we extracted data from patients with a diagnosis of “pure” ET and excluded those with other tremor classifications, including ET-plus, focal, and task-specific tremor, which were formerly considered parts of the ET spectrum.ResultsOut of 653 subjects recruited in the TITAN study by January 2022, the data of 208 (31.8%) “pure” ET patients (86M/122F) were analyzed. The distribution of age at onset was found to be bimodal. The proportion of familial cases by the age-at-onset class of 20 years showed significant differences, with sporadic cases representing the large majority of the class with an age at onset above 60 years. Patients with a positive family history of tremor had a younger onset and were more likely to have leg involvement than sporadic patients despite a similar disease duration. Early-onset and late-onset cases were different in terms of tremor distribution at onset and tremor severity, likely as a function of longer disease duration, yet without differences in terms of quality of life, which suggests a relatively benign progression. Treatment patterns and outcomes revealed that up to 40% of the sample was unsatisfied with the current pharmacological options.DiscussionThe findings reported in the study provide new insights, especially with regard to a possible inversed sex distribution, and to the genetic backgrounds of “pure” ET, given that familial cases were evenly distributed across age-at-onset classes of 20 years. Deep clinical profiling of “pure” ET, for instance, according to age at onset, might increase the clinical value of this syndrome in identifying pathogenetic hypotheses and therapeutic strategies.

Primary familial brain calcification (PFBC) is a rare cerebral microvascular calcifying disorder with a wide spectrum of motor, cognitive, and neuropsychiatric symptoms. It is typically inherited as an autosomal-dominant trait with four causative genes identified so far: SLC20A2, PDGFRB, PDGFB, and XPR1. Our study aimed at screening the coding regions of these genes in a series of 177 unrelated probands that fulfilled the diagnostic criteria for primary brain calcification regardless of their family history. Sequence variants were classified as pathogenic, likely pathogenic, or of uncertain significance (VUS), based on the ACMG-AMP recommendations. We identified 45 probands (25.4%) carrying either pathogenic or likely pathogenic variants (n = 34, 19.2%) or VUS (n = 11, 6.2%). SLC20A2 provided the highest contribution (16.9%), followed by XPR1 and PDGFB (3.4% each), and PDGFRB (1.7%). A total of 81.5% of carriers were symptomatic and the most recurrent symptoms were parkinsonism, cognitive impairment, and psychiatric disturbances (52.3%, 40.9%, and 38.6% of symptomatic individuals, respectively), with a wide range of age at onset (from childhood to 81 years). While the pathogenic and likely pathogenic variants identified in this study can be used for genetic counseling, the VUS will require additional evidence, such as recurrence in unrelated patients, in order to be classified as pathogenic.

Gait abnormalities are common in the elderly and individuals diagnosed with Parkinson’s, often leading to reduced mobility and increased fall risk. Monitoring and assessing gait patterns in these populations play a crucial role in understanding disease progression, early detection of motor impairments, and developing personalized rehabilitation strategies. In particular, by identifying gait irregularities at an early stage, healthcare professionals can implement timely interventions and personalized therapeutic approaches, potentially delaying the onset of severe motor symptoms and improving overall patient outcomes. In this paper, we studied older adults affected by chronic diseases and/or Parkinson’s disease by monitoring their gait due to wearable devices that can accurately detect a person’s movements. In our study, about 50 people were involved in the trial (20 with Parkinson’s disease and 30 people with chronic diseases) who have worn our device for at least 6 months. During the experimentation, each device collected 25 samples from the accelerometer sensor for each second. By analyzing those data, we propose a metric for the “gait quality” based on the measure of entropy obtained by applying the Fourier transform.

Granulocyte-macrophage colony stimulating factor (GM-CSF) and interleukin-4 (IL-4) are cytokines widely used in ex vivo monocyte differentiation experiments, vaccine formulations and disease treatment. The aim of this study was to produce recombinant bovine GM-CSF and IL-4 in an episomal expression system that conserves the postransductional modification of the native proteins and to use the products to differentiate bovine monocytes into dendritic cells.

Osteopontin is a broadly expressed pleiotropic protein, and is attracting increased attention because of its role in the pathophysiology of several inflammatory, degenerative, autoimmune, and oncologic diseases. In fact, in the last decade, several studies have shown that osteopontin contributes to tissue damage not only by recruiting harmful inflammatory cells to the site of lesion, but also increasing their survival. The detrimental role of osteopontin has been indeed well documented in the context of different neurological conditions (i.e., multiple sclerosis, Parkinson’s, and Alzheimer’s diseases). Intriguingly, recent findings show that osteopontin is involved not only in promoting tissue damage (the Yin), but also in repair/regenerative mechanisms (the Yang), mostly triggered by the inflammatory response. These two apparently discordant roles are partly related to the presence of different functional domains in the osteopontin molecule, which are exposed after thrombin or metalloproteases cleavages. Such functional domains may in turn activate intracellular signaling pathways and mediate cell-cell and cell-matrix interactions. This review describes the current knowledge on the Yin and Yang features of osteopontin in nervous system diseases. Understanding the mechanisms behind the Yin/Yang would be relevant to develop highly specific tools targeting this multifunctional protein.

Growing evidence has highlighted that angiotensin-converting enzyme (ACE)-inhibitors (ACEi)/AT1 receptor blockers (ARBs) may influence the complex interplay between dopamine and the renin-angiotensin system in the nigrostriatal pathway, thus affecting the development of levodopa-induced dyskinesia in Parkinson's disease (PD). In the present study, we analyzed whether the use of this class of medication was associated with a reduced occurrence of levodopa-induced dyskinesia, using electronically-stored information of idiopathic PD patients enrolled at Novara University Hospital “Maggiore della Carità". We conducted a retrospective case-control study identifying PD patients with dyskinesias (PwD; n = 47) as cases. For each PwD we selected a non-dyskinetic control (NoD), nearly perfectly matched according to sex, Unified Parkinson's Disease Rating Scale (UPDRS) part III score, and duration of antiparkinsonian treatment. Binary logistic regression was used to evaluate whether dyskinesias were associated with ACEi/ARBs use. Ninety-four PD patients were included, aged 72.18 ± 9 years, with an average disease duration of 10.20 ± 4.8 years and 9.04 ± 4.9 years of antiparkinsonian treatment. The mean UPDRS part III score was 18.87 ± 7.6 and the median HY stage was 2. In the NoD group, 25 (53.2%) were users and 22 (46.8%) non-users of ACEi/ARBs. Conversely, in the PwD group, 11 (23.4%) were users and 36 non-users (76.6%) of this drug class (Pearson chi-square = 8.824, P = 0.003). Concerning general medication, there were no other statistically significant differences between groups. After controlling for tremor dominant phenotype, levodopa equivalent daily dose, HY 3-4, and disease duration, ACEi/ARBs use was a significant predictor of a lower occurrence of dyskinesia (OR = 0.226, 95% CI: 0.080-0.636, P = 0.005). Therefore, our study suggests that ACEi/ARBs may reduce levodopa-induced dyskinesia occurrence and, thanks to good tolerability and easy management, represent a feasible choice when dealing with the treatment of hypertension in PD patients. The study was approved by the Ethics Committee of Novara University Hospital “Maggiore della Carità” (CE 65/16) on July 27, 2016.

Abstract Background In the recent years, clinical progress and better medical assistance for pregnant women, together with the introduction of new complex technologies, has improved the survival of preterm infants. However, this result requires frequent radiological investigations mostly represented by thoracic and abdominal radiographs in incubators. This document was elaborated by an expert panel Italian inter-society working group (Radiologists, Paediatricians, Medical Physicists) with the aim to assist healthcare practitioners in taking choices involving radiation exposures of new-born infants and to provide practical recommendations about justification and optimization in Neonatal Intensive Care Units. The adherence to these practice recommendations could ensure a high quality and patient safety. More complex and less common radiological practice, such as CT scan or fluoroscopy have been excluded. Methods The consensus was reached starting from current good practice evidence shared by four scientific societies panel: AIFM (Italian Association of Physics in Medicine), SIN (Italian Neonatology Society), SIP (Italian Paediatric Society), SIRM (Italian Medical Radiology Society) in order to guarantee good standard practices for every professional involved in Neonatal Intensive Care Units (NICU). The report is divided into clinical and physical-dosimetric sections: clinical Indications, good practice in radiological exposures, devices, exposure parameters and modalities, patient positioning and immobilization, Reference Diagnostic Levels, operators and patient’s radiation protection. Another important topic was the evaluation of the different incubators in order to understand if the consequences of the technological evolution have had an impact on the increase of the dose to the small patients, and how to choose the best device in terms of radiation protection. At the end the working group faced the problem of setting up the correct communication between clinicians and parents following the most recent indications of the international paediatric societies. Results Taking into account the experience and expertise of 10 Italian Centres, the guideline sets out the criteria to ensure a high standard of neonatal care in NICU about procedures, facilities, recommended equipment, quality assurance, radiation protection measures for children and staff members and communication on radiation risk. Conclusions This document will allow a standardization of the approach to the exposures in NICU, although oriented to a flexible methodology.

Lymphocyte count and neutrophil-to-lymphocyte ratio (NLR) may represent useful biomarkers of Parkinson’s disease (PD), but their role in PD-related mild cognitive impairment (MCI) has not been fully elucidated. The present study aimed to confirm whether these immunological measures can discriminate PD patients from healthy controls (HC) and establish their feasibility as prognostic biomarkers of MCI in PD. Immunological data at baseline were analyzed in 58 drug-naïve PD patients and 58 HC matched 1:1 for age, sex, and cardiovascular comorbidities. We selected a subgroup of 51 patients from this initial cohort who underwent longitudinal neuropsychological assessments through the Addenbrooke’s Cognitive Examination Revised (ACE-R) test. We considered the last examination available to analyze the relationship between ACE-R test scores and immunological measures. We found that lymphocyte count was lower and NLR higher in PD than HC (p = 0.006, p = 0.044), with AUC = 0.649 and 0.608, respectively. Secondly, in PD-MCI there were significantly higher levels of circulating lymphocytes (p = 0.002) and lower NLR (p = 0.020) than PD with normal cognitive status (PD-NC). Correlations between lymphocyte count and ACE-R total score and memory subitem (r = −0.382, p = 0.006; r = −0.362, p = 0.01), as well as between NLR and ACE-R total score and memory subitem (r = 0.325, p = 0.02; r = 0.374, p = 0.007), were also found. ROC curve analysis showed that lymphocyte count and NLR displayed acceptable discrimination power of PD-MCI with AUC = 0.759 and 0.691, respectively. In conclusion, we suggest that an altered peripheral immune phenotype could foster cognitive decline development in PD, thus opening the possibility of immune-targeting strategies to tackle this disabling non-motor feature.

COVID-19 was first identified in China in late 2019 and spread globally, originating a pandemic. To limit the spreading of the virus, many countries, including Italy, introduced social distancing measures and limited human movement. The Italian government declared a lockdown of the whole country lasting about two months, and the introduced restrictive rules heavily impacted patients with chronic neurological diseases because of the reduced access to healthcare and community support services. In Parkinson’s disease, studies confirmed lockdown restrictions increase levels of psychological distress, impose limitations on physical activities, and cause a lack of clinical assistance. This study aims at investigating the impact of the pandemic during and beyond the lockdown period in such patients using an online survey. A total of 387 total patients accessed the survey and were asked about their personal experiences during and after lockdown. The results show a significant impact on people’s lives even months after lockdown restrictions were lifted, with a substantial and durable worsening in different aspects of daily life, heavily influenced by impaired access to health services—particularly physical therapies, including personal physical activity—and readily available clinical counselling, with an overall observation of worsening symptoms control. These aspects should be carefully considered in the assessment of global health care strategies to overcome the current pandemic and its broader effects.

Parkinson’s disease (PD) is a common neurodegenerative disease characterized by loss of dopaminergic neurons in the pars compacta of the midbrain substantia nigra. PD pathophysiology is complex, multifactorial, and not fully understood yet. Nonetheless, recent data show that immune system hyperactivation with concomitant production of pro-inflammatory cytokines, both in the central nervous system (CNS) and the periphery, is a signature of idiopathic PD. About 5% of PD patients present an early onset with a determined genetic cause, with either autosomal dominant or recessive inheritance. The involvement of immunity in the genetic forms of PD has been a matter of interest in several recent studies. In this review, we will summarize the main findings of this new and promising field of research

A die for Al alloy casting must be designed to achieve the expected quality levels. Moreover, the casting unit cost must be regarded as the objective function to be minimised. It can be expressed as a function of the quantity of materials and energy to be used, cycle time and equipment investment. This work compares the performance of the die with inserts manufactured using the usual 1.2343 steel with that of the innovative 1.2383. The latter is considered due to its enhanced thermal conductivity, despite being more expensive. Simulation experiments are designed to evaluate different die layouts. The quality design solutions are evaluated against the cost objective function in order to identify the optimal die choice. A case study on gravity die casting (GDC) of an AlSi7Mg0.3 engine head shows faster solidification dynamics when using 1.2383 instead of 1.2343 steel. This reduces the feeder volume, thus increasing the production yield and speeding up the cycle time with a leverage effect. The higher investment cost for the inserts is rapidly returned thanks to the reduction in variable costs. The Return On Investment (ROI) with the improved die in the new solution is short compared with the life of the die.

Introduction: Cervical dystonia (CD) is one of the most common forms of adult-onset isolated dystonia. Recently, CD has been classified according to the site of onset and spread, in different clinical subgroups, that may represent different clinical entities or pathophysiologic subtypes. In order to support this hypothesis, in this study we have evaluated whether different subgroups of CD, that clinically differ for site of onset and spread, also imply different sensorimotor features.Methods: Clinical and demographic data from 842 patients with CD from the Italian Dystonia Registry were examined. Motor features (head tremor and tremor elsewhere) and sensory features (sensory trick and neck pain) were investigated. We analyzed possible associations between motor and sensory features in CD subgroups [focal neck onset, no spread (FNO-NS); focal neck onset, segmental spread (FNO-SS); focal onset elsewhere with segmental spread to neck (FOE-SS); segmental neck involvement without spread (SNI)].Results: In FNO-NS, FOE-SS, and SNI subgroups, head tremor was associated with the presence of tremor elsewhere. Sensory trick was associated with pain in patients with FNO-NS and with head tremor in patients with FNO-SS.Conclusion: The frequent association between head tremor and tremor elsewhere may suggest a common pathophysiological mechanism. Two mechanisms may be hypothesized for sensory trick: a gating mechanism attempting to reduce pain and a sensorimotor mechanism attempting to control tremor.

Background: Amount of parenchymal involvement in patients with interstitial pneumonia Covid-19 related, seems to be associated with a worse prognosis. Nowadays 3D reconstruction imaging is expanding its role in clinical medical practice. We aimed to use 3D lung reconstruction of a young lady affected by Sars-CoV2 infection and interstitial pneumonia, to better visualize, and quantitatively assess the parenchymal involvement.Methods: Volumetric Chest CT scan was performed in a 15 years old girl with interstitial lung pneumonia, Sars-CoV2 infection related. 3D modeling of the lungs, with differentiation of healthy and affected parenchymal area were obtained by using multiple software.Results: 3D reconstruction imaging allowed us to quantify the lung parenchyma involved, Self-explaining 3D images, useful for the understanding, and discussion of the clinical case were also obtained.Conclusions: Quantitative Assessment of Parenchymal Involvement Using 3D Lung Model in Covid-19 Infection is feasible and it provides information which could play a role in the management and risk stratification of these patients.

Abstract Background Parkinson’s disease (PD) affects an estimated 7 to 10 million people worldwide, and only symptomatic treatments are presently available to relieve the consequences of brain dopaminergic neurons loss. Neuronal degeneration in PD is the consequence of neuroinflammation in turn influenced by peripheral adaptive immunity, with CD4+ T lymphocytes playing a key role. CD4+ T cells may however acquire proinflammatory phenotypes, such as T helper (Th) 1 and Th17, as well as anti-inflammatory phenotypes, such as Th2 and the T regulatory (Treg) one, and to what extent the different CD4+ T cell subsets are imbalanced and their functions dysregulated in PD remains largely an unresolved issue. Methods We performed two cross-sectional studies in antiparkinson drug-treated and drug-naïve PD patients, and in age- and sex-matched healthy subjects. In the first one, we examined circulating Th1, Th2, Th17, and in the second one circulating Treg. Number and frequency of CD4+ T cell subsets in peripheral blood were assessed by flow cytometry and their functions were studied in ex vivo assays. In both studies, complete clinical assessment, blood count and lineage-specific transcription factors mRNA levels in CD4+ T cells were independently assessed and thereafter compared for their consistency. Results PD patients have reduced circulating CD4+ T lymphocytes, due to reduced Th2, Th17, and Treg. Naïve CD4+ T cells from peripheral blood of PD patients preferentially differentiate towards the Th1 lineage. Production of interferon-γ and tumor necrosis factor-α by CD4+ T cells from PD patients is increased and maintained in the presence of homologous Treg. This Th1-biased immune signature occurs in both drug-naïve patients and in patients on dopaminergic drugs, suggesting that current antiparkinson drugs do not affect peripheral adaptive immunity. Conclusions The complex phenotypic and functional profile of CD4+ T cell subsets in PD patients strengthen the evidence that peripheral adaptive immunity is involved in PD, and represents a target for the preclinical and clinical assessment of novel immunomodulating therapeutics.

The presence of cats in urban environments has a long history. In Italy, stray cats are protected by national and regional laws, and programs of neutering and reintroduction to colonies are ongoing. Colony cats have been widely studied from a behavioral perspective, while surveys regarding their causes of death are limited, although they may provide relevant information related to public health and cat welfare. This retrospective study provides pathological descriptions and statistical analyses of the causes of death of 186 cats from 100 colonies in the city of Milan. Inflammatory processes represent the primary cause of death (37.7%) and include common feline infectious diseases such as feline panleukopenia (67.5%), particularly in kittens, and feline infectious peritonitis (32.5%), most common in adult cats. Trauma was found to be a common cause of death of young/adult cats (14%) with a generally good body condition, while severe parasitosis was less represented (2.6%). The death of old cats was statistically associated with organ failure (24.7%), particularly renal failure, and tumors (11.8%). Knowledge of the most common causes of death of colony cats could make an important contribution to the health monitoring of these cats and sanitary control of their habitats and provide information on possible related emerging animal welfare concerns.

Parkinson’s disease (PD) is a common and progressive neurodegenerative disease, caused by the loss of dopaminergic neurons in the substantia nigra pars compacta in the midbrain, which is clinically characterized by a constellation of motor and non-motor manifestations. The latter include hyposmia, constipation, depression, pain and, in later stages, cognitive decline and dysautonomia. The main pathological features of PD are neuronal loss and consequent accumulation of Lewy bodies (LB) in the surviving neurons. Alpha-synuclein (α-syn) is the main component of LB, and α-syn aggregation and accumulation perpetuate neuronal degeneration. Mutations in the α-syn gene (SNCA) were the first genetic cause of PD to be identified. Generally, patients carrying SNCA mutations present early-onset parkinsonism with severe and early non-motor symptoms, including cognitive decline. Several SNCA polymorphisms were also identified, and some of them showed association with non-motor manifestations. The functional role of these polymorphisms is only partially understood. In this review we explore the contribution of SNCA and its product, α-syn, in predisposing to the non-motor manifestations of PD.

Parkinson’s disease (PD) is a neurodegenerative disease caused by loss of dopaminergic neurons in the midbrain. PD is clinically characterized by a variety of motor and nonmotor symptoms, and treatment relies on dopaminergic replacement. Beyond a common pathological hallmark, PD patients may present differences in both clinical progression and response to drug therapy that are partly affected by genetic factors. Despite extensive knowledge on genetic variability of dopaminergic receptors (DR), few studies have addressed their relevance as possible influencers of clinical heterogeneity in PD patients. In this review, we summarized available evidence regarding the role of genetic polymorphisms in DR as possible determinants of PD development, progression and treatment response. Moreover, we examined the role of DR in the modulation of peripheral immunity, in light of the emerging role of the peripheral immune system in PD pathophysiology. A better understanding of all these aspects represents an important step towards the development of precise and personalized disease-modifying therapies for PD.

Abstract Enterocutaneous fistulas (ECFs) represent abnormal communications between the gastrointestinal tract and the skin. Nowadays, the majority (~80%) of ECFs develops secondary to abdominal surgeries; alternative, less common causes include chronic inflammatory bowel diseases (IBD) such as Crohn’s disease, tumours, and radiation enteritis in descending order of frequency. These rare disorders require thorough patient assessment and multidisciplinary management to limit the associated morbidity and mortality. This pictorial review includes an overview of causes, clinical manifestations, complications and management of ECFs. Afterwards, the imaging appearances, differential diagnoses, and therapeutic options of post-surgical, IBD-related, and malignant ECFs are presented with case examples. Most of the emphasis is placed on the current pivotal role of CT and MRI, which comprehensively depict ECFs providing cross-sectional information on the underlying postsurgical, neoplastic, infectious, or inflammatory conditions. Radiographic fistulography remains a valid technique, which rapidly depicts the ECF anatomy and confirms communication with the bowel. The aim of this paper is to increase radiologists’ familiarity with ECF imaging, thus allowing an appropriate choice between medical, interventional, or surgical treatment, ultimately resulting in higher likelihood of therapeutic success. Teaching Points • Enterocutaneous fistulas may complicate abdominal surgery, sometimes Crohn’s disease and tumours. • The high associated morbidity and mortality result from sepsis, malnutrition and metabolic imbalance. • The multidisciplinary management of ECFs requires thorough imaging for correct therapeutic choice. • Radiographic fistulography rapidly depicts fistulas and communicating bowel loops in real-time. • Multidetector CT and MRI provide cross-sectional information on fistulas and underlying diseases.

Abstract Despite availability of effective therapies, peptic ulcer disease (PUD) remains a major global disease, resulting from a combination of persistent Helicobacter pylori infection and widespread use of nonsteroidal anti-inflammatory drugs. Albeit endoscopy definitely represents the mainstay diagnostic technique, patients presenting to emergency departments with unexplained abdominal pain generally undergo multidetector CT as an initial investigation. Although superficial ulcers generally remain inconspicuous, careful multiplanar CT interpretation may allow to detect deep ulcers, secondary mural and extraluminal signs of peptic gastroduodenitis, thereby allowing timely endoscopic verification and appropriate treatment. This pictorial essay aims to provide radiologists with an increased familiarity with CT diagnosis of non-perforated PUD, with emphasis on differential diagnosis. Following an overview of current disease epidemiology and complications, it explains the appropriate CT acquisition and interpretation techniques, and reviews with several examples the cross-sectional findings of uncomplicated PUD. Afterwards, the CT features of PUD complications such as ulcer haemorrhage, gastric outlet obstruction, biliary and pancreatic fistulisation are presented. Teaching points • Gastric and duodenal peptic ulcers are increasingly caused by nonsteroidal anti-inflammatory drugs • Multiplanar CT interpretation allows detecting deep ulcers and secondary signs of gastroduodenitis • CT diagnosis of uncomplicated peptic disease relies on direct and indirect signs • Currently the commonest complication, haemorrhage may be treated with transarterial embolisation • Other uncommon complications include gastric outlet obstruction and biliopancreatic fistulisation