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Cow's milk protein allergy (CMPA) is the most common food allergy (FA) in infancy, affecting approximately 2% of children under 4 years of age. According to recent studies, the increasing prevalence of FAs can be associated with changes in composition and function of gut microbiota or "dysbiosis". Gut microbiota regulation, mediated by probiotics, may modulate the systemic inflammatory and immune responses, influencing the development of allergies, with possible clinical benefits. This narrative review collects the actual evidence of probiotics' efficacy in the management of pediatric CMPA, with a specific focus on the molecular mechanisms of action. Most studies included in this review have shown a beneficial effect of probiotics in CMPA patients, especially in terms of achieving tolerance and improving symptoms.
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Hipersensibilidad a los Alimentos , Microbioma Gastrointestinal , Hipersensibilidad a la Leche , Probióticos , Animales , Bovinos , Femenino , Hipersensibilidad a la Leche/terapia , Tolerancia Inmunológica , Probióticos/uso terapéutico , Proteínas de la LecheRESUMEN
Selective IgA deficiency (SIgAD) is the most common human primary immune deficiency (PID). It is classified as a humoral PID characterized by isolated deficiency of IgA (less than 7 mg/dL but normal serum IgG and IgM) in subjects greater than 4 years of age. Intrinsic defects in the maturation of B cells and a perturbation of Th cells and/or cytokine signals have been hypothesized to contribute to SIgAD pathogenesis. The genetic basis of IgA deficiency remains to be clarified. Patients with SIgAD can be either asymptomatic or symptomatic with clinical manifestations including allergy, autoimmunity and recurrent infections mainly of the respiratory and gastrointestinal tract. Studies analyzing allergy on SIgAD patients showed prevalence up to 84%, supporting in most cases the relationship between sIgAD and allergic disease. However, the prevalence of allergic disorders may be influenced by various factors. Thus, the question of whether allergy is more common in SIgAD patients compared to healthy subjects remains to be defined. Different hypotheses support an increased susceptibility to allergy in subjects with SIgAD. Recurrent infections due to loss of secretory IgA might have a role in the pathogenesis of allergy, and vice versa. Perturbation of microbiota also plays a role. The aim of this review is to examine the association between SIgAD and atopic disease and to update readers on advances over time at this important interface between allergy and SIgAD.
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Hipersensibilidad , Deficiencia de IgA , Autoinmunidad , Linfocitos B , Humanos , Hipersensibilidad/epidemiología , Deficiencia de IgA/complicaciones , Deficiencia de IgA/epidemiología , PrevalenciaRESUMEN
Gastrointestinal (GI) symptoms can originate from severe dysmotility due to enteric neuropathies. Current methods used to demonstrate enteric neuropathies are based mainly on classic qualitative histopathological/immunohistochemical evaluation. This study was designed to identify an objective morphometric method for paraffin-embedded tissue samples to quantify the interganglionic distance between neighboring myenteric ganglia immunoreactive for neuron-specific enolase, as well as the number of myenteric and submucosal neuronal cell bodies/ganglion in jejunal specimens of patients with severe GI dysmotility. Jejunal full-thickness biopsies were collected from 32 patients (22 females; 16-77 yr) with well-characterized severe dysmotility and 8 controls (4 females; 47-73 yr). A symptom questionnaire was filled before surgery. Mann-Whitney U test, Kruskal-Wallis coupled with Dunn's posttest and nonparametric linear regression tests were used for analyzing morphometric data and clinical correlations, respectively. Compared with controls, patients with severe dysmotility exhibited a significant increase in myenteric interganglionic distance (P = 0.0005) along with a decrease in the number of myenteric (P < 0.00001) and submucosal (P < 0.0004) neurons. A 50% reduction in the number of submucosal and myenteric neurons correlated with an increased interganglionic distance and severity of dysmotility. Our study proposes a relatively simple tool that can be applied for quantitative evaluation of paraffin sections from patients with severe dysmotility. The finding of an increased interganglionic distance may aid diagnosis and limit the direct quantitative analysis of neurons per ganglion in patients with an interganglionic distance within the control range.NEW & NOTEWORTHY Enteric neuropathies are challenging conditions characterized by a severe impairment of gut physiology, including motility. An accurate, unambiguous assessment of enteric neurons provided by quantitative analysis of routine paraffin sections may help to define neuropathy-related gut dysmotility. We showed that patients with severe gut dysmotility exhibited an increased interganglionic distance associated with a decreased number of myenteric and submucosal neurons, which correlated with symptoms and clinical manifestations of deranged intestinal motility.
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Motilidad Gastrointestinal/fisiología , Enfermedades Intestinales , Intestinos , Plexo Mientérico , Proteínas del Tejido Nervioso , Manejo de Especímenes/métodos , Plexo Submucoso , Correlación de Datos , Femenino , Humanos , Inmunohistoquímica , Enfermedades Intestinales/inmunología , Enfermedades Intestinales/patología , Enfermedades Intestinales/fisiopatología , Intestinos/inervación , Intestinos/patología , Intestinos/fisiopatología , Masculino , Persona de Mediana Edad , Plexo Mientérico/inmunología , Plexo Mientérico/patología , Proteínas del Tejido Nervioso/análisis , Proteínas del Tejido Nervioso/inmunología , Plexo Submucoso/inmunología , Plexo Submucoso/patologíaRESUMEN
BACKGROUND & AIMS: Chronic intestinal pseudo-obstruction (CIPO) is characterized by severe intestinal dysmotility that mimics a mechanical subocclusion with no evidence of gut obstruction. We searched for genetic variants associated with CIPO to increase our understanding of its pathogenesis and to identify potential biomarkers. METHODS: We performed whole-exome sequencing of genomic DNA from patients with familial CIPO syndrome. Blood and lymphoblastoid cells were collected from patients and controls (individuals without CIPO); levels of messenger RNA (mRNA) and proteins were analyzed by quantitative reverse-transcription polymerase chain reaction, immunoblot, and mobility shift assays. Complementary DNAs were transfected into HEK293 cells. Expression of rad21 was suppressed in zebrafish embryos using a splice-blocking morpholino (rad21a). Gut tissues were collected and analyzed. RESULTS: We identified a homozygous mutation (p.622, encodes Ala>Thr) in RAD21 in patients from a consanguineous family with CIPO. Expression of RUNX1, a target of RAD21, was reduced in cells from patients with CIPO compared with controls. In zebrafish, suppression of rad21a reduced expression of runx1; this phenotype was corrected by injection of human RAD21 mRNA, but not with the mRNA from the mutated p.622 allele. rad21a Morpholino zebrafish had delayed intestinal transit and greatly reduced numbers of enteric neurons, similar to patients with CIPO. This defect was greater in zebrafish with suppressed expression of ret and rad21, indicating their interaction in the regulation of gut neurogenesis. The promoter region of APOB bound RAD21 but not RAD21 p.622 Ala>Thr; expression of wild-type RAD21 in HEK293 cells repressed expression of APOB, compared with control vector. The gut-specific isoform of APOB (APOB48) is overexpressed in sera from patients with CIPO who carry the RAD21 mutation. APOB48 also is overexpressed in sporadic CIPO in sera and gut biopsy specimens. CONCLUSIONS: Some patients with CIPO carry mutations in RAD21 that disrupt the ability of its product to regulate genes such as RUNX1 and APOB. Reduced expression of rad21 in zebrafish, and dysregulation of these target genes, disrupts intestinal transit and the development of enteric neurons.
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Apolipoproteína B-100/genética , Proteínas de Ciclo Celular/genética , Subunidad alfa 2 del Factor de Unión al Sitio Principal/genética , Sistema Nervioso Entérico/metabolismo , Motilidad Gastrointestinal/genética , Seudoobstrucción Intestinal/genética , Proteínas Nucleares/genética , Fosfoproteínas/genética , ARN Mensajero/genética , Proteínas de Pez Cebra/genética , Adulto , Animales , Estudios de Casos y Controles , Enfermedad Crónica , Proteínas de Unión al ADN , Sistema Nervioso Entérico/fisiopatología , Femenino , Perfilación de la Expresión Génica , Técnicas de Silenciamiento del Gen , Células HEK293 , Humanos , Seudoobstrucción Intestinal/fisiopatología , Masculino , Persona de Mediana Edad , Análisis de Secuencia de ADN , Adulto Joven , Pez CebraRESUMEN
Food supplements are defined as foodstuffs the purpose of which is to supplement the normal diet and which are concentrated sources of nutrients or other substances with a nutritional or physiological effect, often referred to as nutraceuticals, may exert benefit to the human body. Their use is increasing worldwide, including Europe and in Italy. However, some doctors are skeptical about their effectiveness and safety. This reluctance may depend on poor knowledge of the mechanisms of action and clinical evidence in literature. The Italian Society of Pediatric Allergy and Immunology (SIAIP) promoted the institution of an ad hoc Committee. The first initiative performed by this Committee was the administration of a questionnaire to the members of SIAIP.The results of this survey provided interesting results. Most pediatricians know the food supplement concept but frequently need help understanding the mechanisms of action. Most prescribe food supplements, mainly for preventing infections or enhancing immune defense. In addition, they prefer to use food supplements as cycles or add-on therapy. Finally, most participants like to attend events on this issue and contribute to new evidence through trials.In conclusion, this survey underscores the relevance of food supplement issues and attests to interest in this topic. However, there is a need to provide information and promote studies on this matter.
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Suplementos Dietéticos , Sociedades Médicas , Humanos , Italia , Encuestas y Cuestionarios , Actitud del Personal de Salud , Niño , Alergia e Inmunología , Pediatría , Pautas de la Práctica en Medicina , Masculino , Pediatras , FemeninoRESUMEN
The prevalence of allergic diseases has dramatically increased among children in recent decades. These conditions significantly impact the quality of life of allergic children and their families. Lactoferrin, a multifunctional glycoprotein found in various biological fluids, is emerging as a promising immunomodulatory agent that can potentially alleviate allergic diseases in children. Lactoferrin's multifaceted properties make it a compelling candidate for managing these conditions. Firstly, lactoferrin exhibits potent anti-inflammatory and antioxidant activities, which can mitigate the chronic inflammation characteristic of allergic diseases. Secondly, its iron-binding capabilities may help regulate the iron balance in allergic children, potentially influencing the severity of their symptoms. Lactoferrin also demonstrates antimicrobial properties, making it beneficial in preventing secondary infections often associated with respiratory allergies. Furthermore, its ability to modulate the immune response and regulate inflammatory pathways suggests its potential as an immune-balancing agent. This review of the current literature emphasises the need for further research to elucidate the precise roles of lactoferrin in allergic diseases. Harnessing the immunomodulatory potential of lactoferrin could provide a novel add-on approach to managing allergic diseases in children, offering hope for improved outcomes and an enhanced quality of life for paediatric patients and their families. As lactoferrin continues to capture the attention of researchers, its properties and diverse applications make it an intriguing subject of study with a rich history and a promising future.
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Hipersensibilidad , Lactoferrina , Enfermedades Respiratorias , Niño , Humanos , Antiinflamatorios/uso terapéutico , Antioxidantes/uso terapéutico , Hipersensibilidad/tratamiento farmacológico , Lactoferrina/uso terapéutico , Calidad de Vida , Enfermedades Respiratorias/tratamiento farmacológicoRESUMEN
BACKGROUND: We followed the effects of a new SCIT with a chemically polymerized allergen Alt a1, evaluating the trend of clinical and functional parameters in an observational-prospective study. METHODS: 42 children with AR and intermittent asthma sensitized to A.A.: 17 patients started SCIT (Modigoid®), and 25 continued symptomatic therapy. At the initial visit (T0), all patients performed total IgE (tIgE) and specific IgE (sIgE) for Alt a1, nasal nitric oxide (nFeNo), nasal cytology, anterior active rhinomanometry (AAR) and spirometry. After 24 months (T1), they repeated the same procedures as in T0. RESULTS: Patients treated with Modigoid presented a statistically significant (p < 0.001) reduction of nFeNO (T0:1651.06 ± 149.18; T1: 1394.12 ± 108.98), tIgE (T0: 311.48 ± 144.18; T1: 164.73 ± 50.69), sIgE for Alt a1 (T0: 28.59 ± 12.69; T1: 19.54 ± 7.37), an improvement of nasal airflow (T0: 71.62 ± 8.66; T1: 95.12 ± 5.91), nasal eosinophils (T0: 20.59 ± 2.35; T1: 14.88 ± 1.65) and FEV1 (T0: 95.58 ± 7.91; T1: 116.64 ± 5.94). CONCLUSIONS: The new SCIT for Alt a1 significantly improves AR symptoms from a subjective, objective point of view and laboratory and functional parameters.
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Kiwifruit allergy is an emerging pathological condition in both general and pediatric populations with a wide range of symptoms linked to variable molecular patterns, justifying systemic and cross-reactions with other allergens (i.e., latex, pollen, and fruit). Skin prick test (SPT), specific serum IgE (Act d 1, Act d 2, Act d 5, Act d 8, and Act d 10) directed against five out of thirteen molecular allergens described in the literature, and oral test challenge with kiwifruit are available for defining diagnosis. The management is similar to that of other food allergies, mostly based on an elimination diet. Although kiwi allergy has been on the rise in recent years, few studies have evaluated the clinical characteristics and methods of investigating this form of allergy. Data collected so far show severe allergic reaction to be more frequent in children compared to adults. Therefore, the aim of this review is to collect the reported clinical features and the available association with specific molecular patterns of recognition to better understand how to manage these patients and improve daily clinical practice.
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Actinidia , Hipersensibilidad a los Alimentos , Adulto , Humanos , Niño , Inmunoglobulina E , Hipersensibilidad a los Alimentos/diagnóstico , Alérgenos , Frutas , PolenRESUMEN
We carefully read the correspondence [...].
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BACKGROUND: Selective IgA deficiency (SIgAD) is the most common inborn error of immunity. The exact prevalence and pathogenesis of allergy in SIgAD have not yet been defined. We aimed to describe the prevalence and the characteristics of allergy in pediatric SIgAD subjects, evaluate the association between allergy and other comorbidities, and define the immune phenotype of allergic and non-allergic patients. METHODS: Clinical and immunological data from 67 SIgAD patients were collected over a 13-year period at a single center. Patients' characteristics were analyzed according to the presence of allergy. RESULTS: Allergy was diagnosed in 34% of SIgAD patients, with a median age at allergy diagnosis of 8 years. Allergy was the second-most-common clinical manifestation, following recurrent respiratory infections. Among the allergic group, 74% had rhinitis, 30% asthma, 30% atopic dermatitis, and 22% food allergy; one out of three had more than one allergic manifestation. SIgAD patients showed more frequent transitory lymphopenia and a lower count of CD19+ at diagnosis than at last FU. However, compared to non-allergic subjects, allergic patients did not differ in their immune phenotype, number and severity of infections, or increased autoimmunity. CONCLUSIONS: In our longitudinal study, compared to non-allergic SIgAD patients, those with allergies did not present a more severe immune defect or complex clinical phenotype. However, evaluation and early identification of allergy in the context of SIgAD assessment, both at diagnosis and during FU, and definition of a proper management are important to prevent complications and improve the patient's quality of life.
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BACKGROUND: Between June and July 2020, we evaluated children and adolescents concerning post-infection surveillance after a COVID-19 positivity during the lockdown. We aimed to assess whether the anamnestic presence of allergies could correlate with the presence of SARS-CoV-2 symptoms, and in particular with anosmia. MATERIAL AND METHODS: For each patient, we collected anamnestic data, the presence of allergies documented by performing skin prick tests, and COVID-19 symptoms. Then, if over six years of age, each patient underwent an active anterior rhinomanometry. RESULTS: A total of 296 patients were enrolled, of whom 105 (35.4%) reported allergies. Considering COVID-19 symptoms, 74 subjects (25%) presented an asymptomatic form, 222 (75%) reported symptoms, and anosmia recurred in 60 subjects (27.03%). A statistically significant relationship was found between allergies and symptomatic COVID-19 (p = 0.042), allergies, and anosmia (p = 0.05), and allergies and anosmia in males (p = 0.007). Moreover, anosmic patients presented a higher body mass index, older age, and a longer COVID-19 duration with statistical significance (p = 0.001, 0.001, 0.006, respectively). CONCLUSIONS: Allergic subjects seem to develop symptomatic COVID-19 more frequently and allergies appear to be a protective factor from anosmia's onset in males.
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Starting from the "Hygiene Hypothesis" to the "Microflora hypothesis" we provided an overview of the symbiotic and dynamic equilibrium between microbiota and the immune system, focusing on the role of dysbiosis in atopic march, particularly on allergic rhinitis. The advent of deep sequencing technologies and metabolomics allowed us to better characterize the microbiota diversity between individuals and body sites. Each body site, with its own specific environmental niches, shapes the microbiota conditioning colonization and its metabolic functionalities. The analysis of the metabolic pathways provides a mechanistic explanation of the remote mode of communication with systems, organs, and microflora of other body sites, including the ecosystem of the upper respiratory tract. This axis may have a role in the development of respiratory allergic disease. Notably, the microbiota is significant in the development and maintenance of barrier function; influences hematopoiesis and innate immunity; and shows its critical roles in Th1, Th2, and Treg production, which are necessary to maintain immunological balance and promote tolerance, taking part in every single step of the inflammatory cascade. These are microbial biotherapy foundations, starting from probiotics up to postbiotics and parabiotics, in a still-ongoing process. When considering the various determinants that can shape microbiota, there are several factors to consider: genetic factors, environment, mode of delivery, exposure to antibiotics, and other allergy-unrelated diseases. These factors hinder the engraftment of probiotic strains but may be upgradable with postbiotic and parabiotic administration directly on molecular targets. Supplementation with postbiotics and parabiotics could represent a very exciting perspective of treatment, bypassing probiotic limitations. At present, this avenue remains theoretical and to be explored, but it will certainly be a fascinating path to follow.
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The pathogenetic mechanisms underlying gastrointestinal dysmotility in diabetic patients remain poorly understood, although enteric neuropathy, damage to interstitial cells of Cajal (ICC) and smooth muscle cell injury are believed to play a role. The aim of this study was to investigate the morphological and functional changes underlying intestinal dysmotility in RIP-I/hIFNß transgenic mice treated with multiple very low doses of streptozotocin (20 mg/kg, i.p., 5 days). Compared with vehicle-treated mice, streptozotocin-treated animals developed type 1 diabetes mellitus, with sustained hyperglycaemia for 3.5 months, polyphagia, polydipsia and increased faecal output without changes in faecal water content (metabolic cages). Diabetic mice had a longer intestine, longer ileal villi and wider colonic crypts (conventional microscopy) and displayed faster gastric emptying and intestinal transit. Contractility studies showed selective impaired neurotransmission in the ileum and mid-colon of diabetic mice. Compared with controls, the ileal and colonic myenteric plexus of diabetic mice revealed ultrastructural features of neuronal degeneration and HuD immunohistochemistry on whole-mount preparations showed 15% reduction in neuronal numbers. However, no immunohistochemical changes in apoptosis-related markers were noted. Lower absolute numbers of neuronal nitric oxide synthase- and choline acetyltransferase-immunopositive neurons and enhanced vasoactive intestinal polypeptide and substance P immunopositivity were observed. Ultrastructural and immunohistochemical analyses did not reveal changes in the enteric glial or ICC networks. In conclusion, this model of diabetic enteropathy shows enhanced intestinal transit associated with intestinal remodelling, including neuroplastic changes, and overt myenteric neuropathy. Such abnormalities are likely to reflect neuroadaptive and neuropathological changes occurring in this diabetic model.
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Colon/patología , Colon/fisiopatología , Diabetes Mellitus Experimental/fisiopatología , Diabetes Mellitus Tipo 1/fisiopatología , Motilidad Gastrointestinal/fisiología , Íleon/patología , Íleon/fisiopatología , Animales , Colina O-Acetiltransferasa/metabolismo , Colon/metabolismo , Diabetes Mellitus Experimental/inducido químicamente , Diabetes Mellitus Experimental/patología , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/patología , Neuropatías Diabéticas/metabolismo , Neuropatías Diabéticas/patología , Neuropatías Diabéticas/fisiopatología , Modelos Animales de Enfermedad , Vaciamiento Gástrico/fisiología , Íleon/metabolismo , Interferón beta/genética , Interferón beta/metabolismo , Masculino , Ratones , Ratones Transgénicos , Plexo Mientérico/metabolismo , Plexo Mientérico/patología , Plexo Mientérico/fisiopatología , Óxido Nítrico Sintasa de Tipo I/metabolismo , Proteína Serina-Treonina Quinasas de Interacción con Receptores/genética , Proteína Serina-Treonina Quinasas de Interacción con Receptores/metabolismo , Estreptozocina/efectos adversos , Sustancia P/metabolismo , Péptido Intestinal Vasoactivo/metabolismoRESUMEN
BACKGROUND: During the lockdown period caused by the SARS-CoV-2 pandemic, we monitored via online survey the trend of allergic symptoms and the therapeutic compliance in patients followed at our center. MATERIAL AND METHODS: In June 2020, we selected children followed at the Allergy and Immunology Service of Umberto I Hospital, aged between 6 and 16 years old, diagnosed with asthma and/or rhinitis and sensitized to grass pollen or dust mite. We sent an email with 12 multiple-choice questions investigating several areas: type of disease and sensitization, recurrence of symptoms, medication use during lockdown compared to the same period of the previous year. RESULTS: The results of 82 questionnaires showed that 17.8% of patients suffered from asthma, 24.4% from rhinitis, and 57.8% from both. Within the group of asthmatic children, most of them presented an improvement of their symptoms. Likewise, with regard to allergic rhinitis, most of them reported better clinical conditions. Regarding treatment, we observed a global decrease in the use of on-demand therapies (salbutamol, nasal corticosteroid, and antihistamine) for both pathologies. In addition, there was a reduction in the use of basal therapy for asthma and rhinitis from 2019 (23.3%) to 2020 (15.5%). CONCLUSIONS: Our data show a general trend of clinical improvement and a reduction in the use of on-demand and basal therapy in allergic children during the lockdown.
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BACKGROUND: Allergic rhinitis (AR) and adenoidal hypertrophy (AH) are the most frequent causative disorders of nasal obstruction in children, leading to recurrent respiratory infections. Both nasal cavities are colonized by a stable microbial community susceptible to environmental changes and Staphylococcus aureus seems to play the major role. Furthermore, nasal microbiota holds a large number and variety of viruses with upper respiratory tract infections. This local microbiota deserves attention because its modification could induce a virtuous cross-talking with the immune system, with a better clearance of pathogens. Although AR and AH present a different etiopathogenesis, they have in common a minimal chronic inflammation surrounding nasal obstruction; hence it would be challenging to evaluate the effect of an immunomodulator on this minimal chronic inflammation with possible clinical and microbiological effects. The aim of this study is therefore to evaluate the efficacy of an immunomoldulator (Pidotimod) on nasal obstruction in children with AR and/or AH and whether its action involves a variation of nasal microbiota. METHODS: We enrolled 76 children: those with allergic rhinitis (AR) sensitized to dust mites entered the AR group, those with adenoidal hypertrophy (AH) the AH group, those with both conditions the AR/AH group and those without AR ± AH as controls (CTRL). At the first visit they performed: skin prick tests, nasal fiberoptic endoscopy, anterior rhinomanometry, nasal swabs. Children with. AR ± AH started treatment with Pidotimod. After 1 month they were re-evaluated performing the same procedures. The primary outcome was the evaluation of nasal obstruction after treatment and the secondary outcome was the improvement of symptoms and the changes in nasal microflora. RESULTS: All patients improved their mean nasal flow (mNF) in respect to the baseline. In AR children mNF reached that one of CTRL. In AH children±AR the mNF was lower in respect to CTRL and AR group. We did not find any differences among all the groups at the two different time points in nasal microflora. CONCLUSIONS: Pidotimod is able to give an improvement in nasal obstruction, especially in AR children but this effect seems to be not mediated by changes in nasal microbiota.
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Tonsila Faríngea/patología , Factores Inmunológicos/uso terapéutico , Obstrucción Nasal/tratamiento farmacológico , Ácido Pirrolidona Carboxílico/análogos & derivados , Rinitis Alérgica/tratamiento farmacológico , Tiazolidinas/uso terapéutico , Factores de Edad , Niño , Femenino , Humanos , Hipertrofia , Italia , Masculino , Obstrucción Nasal/etiología , Ácido Pirrolidona Carboxílico/uso terapéutico , Rinitis Alérgica/complicaciones , Resultado del TratamientoRESUMEN
Anosmia is a well-described symptom of Corona Virus Disease 2019 (COVID-19). Several respiratory viruses are able to cause post-viral olfactory dysfunction, suggesting a sensorineural damage. Since the olfactory bulb is considered an immunological organ contributing to prevent the invasion of viruses, it could have a role in host defense. The inflammatory products locally released in COVID-19, leading to a local damage and causing olfactory loss, simultaneously may interfere with the viral spread into the central nervous system. In this context, olfactory receptors could play a role as an alternative way of SARS-CoV-2 entry into cells locally, in the central nervous system, and systemically. Differences in olfactory bulb due to sex and age may contribute to clarify the different susceptibility to infection and understand the role of age in transmission and disease severity. Finally, evaluation of the degree of functional impairment (grading), central/peripheral anosmia (localization), and the temporal course (evolution) may be useful tools to counteract COVID-19.
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BACKGROUND: Gastrointestinal (GI) and extra-GI symptoms/manifestations represent key clinical features of patients with non-celiac gluten/wheat sensitivity (NCG/WS). This study aimed to investigate neuro-immune (focusing on mast cells, MCs) interactions in the duodenal submucosa of patients with NCG/WS. METHODS: Submucosal whole mounts from duodenal biopsies of 34 patients with self-reported NCG/WS, 28 with celiac disease (CD), 13 with functional dyspepsia (FD), and 24 healthy controls (HC) were analyzed by immunohistochemistry. Quantitative data on neuronal and MCs density and the percentage of MCs in close vicinity to nerves were obtained, and correlations among neurons, MC density and MC-nerve distance (D), and symptoms were assessed in the three groups. KEY RESULTS: The number of submucosal neurons was not different among groups. In NCG/WS, MC density was not different from HC, while it was slightly increased vs. CD (P = .07) and significantly decreased vs. FD (P < .05). The percentage of MCs close to nerves (D < 15 µm) was similarly increased in all three pathological groups vs. HC (P < .001). In NCG/WS, MC infiltration correlated with bloating (P = .001) and abdominal pain severity (P = .03) and the percentage of MCs in proximity to neurons correlated with the number of GI symptoms (D < 5 µm; P = .05), bloating and abdominal pain severity (D < 15um; P = .01). CONCLUSIONS AND INFERENCES: Submucosal MC infiltration and the close (within 15 µm) MC-to-nerve proximity in the duodenum of NCG/WS patients are features providing a histopathological basis to better understand GI symptoms in this condition.
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Dolor Abdominal/inmunología , Glútenes/efectos adversos , Mastocitos/inmunología , Neuronas/inmunología , Hipersensibilidad al Trigo/inmunología , Dolor Abdominal/etiología , Dolor Abdominal/patología , Adolescente , Adulto , Duodeno/inmunología , Duodeno/patología , Femenino , Glútenes/inmunología , Humanos , Masculino , Mastocitos/patología , Persona de Mediana Edad , Neuronas/patología , Índice de Severidad de la Enfermedad , Hipersensibilidad al Trigo/complicaciones , Adulto JovenRESUMEN
BACKGROUND: Chronic intestinal pseudo-obstruction (CIPO) is a rare condition due to severe impairment of gut motility responsible for recurrent subocclusive episodes. Although neuromuscular-glial-ICC abnormalities represent the main pathogenetic mechanism, the pathophysiology of CIPO remains poorly understood. Intestinal epithelial and vascular endothelial barrier (IEVB) abnormalities can contribute to neuroepithelial changes by allowing passage of harmful substances. METHODS: To test retrospectively whether IEVB defects occur in patients with CIPO, we measured the jejunal protein expression of the major tight junction (TJ) components. CIPO patients were subdivided according to gut neuromuscular histopathology: apparently normal (AN); with inflammation (INF); or with degenerative alterations (DEG). The presence of occludin/claudin oligomers (index of TJ assembly), the amount of occludin, claudin-4, and zonula occludens-1 (ZO-1), and the expression of vasoactive intestinal polypeptide (VIP) and glial fibrillary acidic protein (GFAP) immunoreactivities were evaluated on jejunal full-thickness biopsies using Western blot. KEY RESULTS: Oligomers were absent in the 73% of CIPO. Total occludin decreased in CIPO with AN and INF changes. Claudin-4 was upregulated in CIPO with INF and DEG features. ZO-1 and VIP expression decreased selectively in DEG group. GFAP increased in CIPO regardless the histopathological phenotype. CONCLUSIONS & INFERENCES: The absence of oligomers demonstrated in our study suggests that IEBV is altered in CIPO. The mechanism leading to oligomerization is occludin-dependent in AN and INF, whereas is ZO-1-dependent in DEG. Our study provides support to IEVB abnormalities contributing to CIPO clinical and histopathological features.
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Mucosa Intestinal/patología , Seudoobstrucción Intestinal/patología , Proteínas de Uniones Estrechas/metabolismo , Adolescente , Adulto , Anciano , Enfermedad Crónica , Femenino , Humanos , Mucosa Intestinal/metabolismo , Seudoobstrucción Intestinal/metabolismo , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Uniones Estrechas/metabolismo , Uniones Estrechas/patología , Adulto JovenRESUMEN
BACKGROUND: Chronic intestinal pseudo-obstruction (CIPO) and enteric dysmotility (ED) are severe intestinal motility disorders usually associated with underlying neuromuscular abnormalities. OBJECTIVE: To evaluate the in vitro neuromuscular function of patients with severe intestinal motility disorders. METHODS: Full-thickness intestinal biopsies (16 jejunum and 3 ileum) obtained from patients with CIPO (n = 10) and ED (n = 9) were studied using muscle bath and microelectrode techniques. Control samples (n = 6 ileum and n = 6 jejunum) were used to establish the range of normality. KEY RESULTS: Fourteen parameters were defined to assess muscle contractility and nerve-muscle interaction: five to evaluate smooth muscle and interstitial cells of Cajal (ICC) and nine to evaluate inhibitory neuromuscular transmission. For each sample, a parameter was scored 0 if the value was inside the normal range or a value of 1 if it was outside. Patients' samples (CIPO/ED) had more abnormal parameters than controls (P < 0.001 for both jejunum and ileum). Functional abnormalities were found to be heterogeneous. The most prevalent abnormality was a decreased purinergic neuromuscular transmission, which was detected in 43.8% of jejunal samples. CONCLUSIONS AND INFERENCES: Abnormalities of neuromuscular intestinal function are detected in vitro in severe intestinal dysmotility. However, consistent with the heterogeneity of the disease pathophysiology, functional impairment cannot be attributed to a single mechanism. Specifically, defects of purinergic neuromuscular transmission may have an important role in motility disorders of the gastrointestinal tract.
Asunto(s)
Motilidad Gastrointestinal/fisiología , Enfermedades Intestinales/fisiopatología , Músculo Liso/fisiopatología , Unión Neuromuscular/fisiopatología , Transmisión Sináptica/fisiología , Adolescente , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Contracción Muscular/fisiología , Adulto JovenRESUMEN
Experimental evidence indicates that chronic mechanical sub-occlusion of the intestine may damage the enteric nervous system (ENS), although data in humans are lacking. We here describe the first case of enteric degenerative neuropathy related to a congenital obstruction of the gut. A 3-year and 9-mo old girl began to complain of vomiting, abdominal distension, constipation with air-fluid levels at plane abdominal radiology. Her subsequent medical history was characterized by 3 operations: the first showed dilated duodeno-jejunal loops in the absence of occlusive lesions; the second (2 years later) was performed to obtain full-thickness biopsies of the dilated intestinal loops and revealed hyperganglionosis at histopathology; the third (9 years after the hyperganglionosis was identified) disclosed a Ladd's band which was removed and the associated gut malrotation was corrected. Repeated intraoperative full-thickness biopsies showed enteric degenerative neuropathy along with reduced interstitial cells of Cajal network in dilated loops above the obstruction and a normal neuromuscular layer below the Ladd's band. One year after the latest surgery the patient tolerated oral feeding and did well, suggesting that congenital (partial) mechanical obstruction of the small bowel in humans can evoke progressive adaptive changes of the ENS which are similar to those found in animal models of intestinal mechanical occlusion. Such ENS changes mimic neuronal abnormalities observed in intestinal pseudo-obstruction.