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The pig is an important translational model for studying intestinal physiology and disorders for its many homologies with humans, including the organization of the enteric nervous system (ENS), the major regulator of gastrointestinal functions. This study focused on the quantification and neurochemical characterization of substance P (SP) neurons in the pig ascending (AC) and descending colon (DC) in wholemount preparations of the inner submucosal plexus (ISP), outer submucosal plexus (OSP), and myenteric plexus (MP). We used antibodies for the pan-neuronal marker HuCD, and choline acetyltransferase (ChAT) and neuronal nitric oxide synthase (nNOS), markers for excitatory and inhibitory transmitters, for multiple labeling immunofluorescence and high-resolution confocal microscopy. The highest density of SP immunoreactive (IR) neurons was in the ISP (222/mm2 in the AC, 166/mm2 in the DC), where they make up about a third of HuCD-IR neurons, compared to the OSP and MP (19-22% and 13-17%, respectively, P < 0.001-0.0001). HuCD/SP/ChAT-IR neurons (up to 23%) were overall more abundant than HuCD/SP/nNOS-IR neurons (< 10%). Most SP-IR neurons contained ChAT-IR (62-85%), whereas 18-38% contained nNOS-IR with the highest peak in the OSP. A subpopulation of SP-IR neurons contains both ChAT- and nNOS-IR with the highest peak in the OSP and ISP of DC (33-36%) and the lowest in the ISP of AC (< 10%, P < 0.001). SP-IR varicose fibers were abundant in the ganglia. This study shows that SP-IR neurons are functionally distinct with variable proportions in different plexuses in the AC and DC reflecting diverse functions of specific colonic regions.
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Plexo Mientérico , Plexo Submucoso , Humanos , Suínos , Animais , Substância P , Neurônios , Colo , Colina O-AcetiltransferaseRESUMO
BACKGROUND: Pediatric chronic intestinal pseudo-obstruction (PIPO) is a rare disease characterized by symptoms and radiological signs suggestive of intestinal obstruction, in the absence of lumen-occluding lesions. It results from an extremely severe impairment of propulsive motility. The intestinal endocrine system (IES) jointly with the enteric nervous system (ENS) regulates secreto-motor functions via different hormones and bioactive messengers/neurotransmitters. The neurotransmitter 5-hydroxytryptamine (5-HT) (or serotonin) is linked to intestinal peristalsis and secretory reflexes. Gut microbiota and its interplay with ENS affect 5-HT synthesis, release, and the subsequent serotonin receptor activation. To date, the interplay between 5-HT and gut microbiota in PIPO remains largely unclear. This study aimed to assess correlations between mucosa associated microbiota (MAM), intestinal serotonin-related genes expression in PIPO. To this purpose, biopsies of the colon, ileum and duodenum have been collected from 7 PIPO patients, and 7 age-/sex-matched healthy controls. After DNA extraction, the MAM was assessed by next generation sequencing (NGS) of the V3-V4 region of the bacterial RNA 16 S, on an Illumina Miseq platform. The expression of genes implicated in serotoninergic pathway (TPH1, SLC6A4, 5-HTR3 and 5-HTR4) was established by qPCR, and correlations with MAM and clinical parameters of PIPO have been evaluated. RESULTS: Our results revealed that PIPO patients exhibit a MAM with a different composition and with dysbiosis, i.e. with a lower biodiversity and fewer less connected species with a greater number of non-synergistic relationships, compared to controls. qPCR results revealed modifications in the expression of serotonin-related intestinal genes in PIPO patients, when compared to controls. Correlation analysis do not reveal any kind of connection. CONCLUSIONS: For the first time, we report in PIPO patients a specific MAM associated to underlying pathology and an altered intestinal serotonin pathway. A possible dysfunction of the serotonin pathway, possibly related to or triggered by an altered microbiota, may contribute to dysmotility in PIPO patients. The results of our pilot study provide the basis for new biomarkers and innovative therapies targeting the microbiota or serotonin pathways in PIPO patients.
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Microbioma Gastrointestinal , Pseudo-Obstrução Intestinal , Humanos , Criança , Serotonina/metabolismo , Projetos Piloto , Intestinos , Pseudo-Obstrução Intestinal/genética , Pseudo-Obstrução Intestinal/diagnóstico , Proteínas da Membrana Plasmática de Transporte de SerotoninaRESUMO
BACKGROUND: Zonulin is involved in the integrity and functioning of both intestinal-epithelial barrier and blood-brain barrier (BBB) by regulating tight junction molecular assembly. AIM: Since changes in microbiota and BBB may play a role in neurodegenerative disorders, we aimed to determine whether serum zonulin levels change in older patients affected by different types of dementia or mild cognitive impairment (MCI). METHODS: We evaluated serum zonulin levels in patients with late-onset AD (LOAD), vascular dementia (VAD), MIXED (AD + VAD) dementia, amnestic MCI, and in healthy controls. RESULTS: Compared with controls, serum zonulin increased in LOAD, MIXED dementia, and aMCI but not in VAD, independent of potential confounders (ANCOVA p = 0.01; LOAD vs controls, p = 0.01; MIXED vs. controls, p = 0.003; aMCI vs. controls, p = 0.04). Notably, aMCI converting to dementia showed significantly higher levels of zonulin compared with stable aMCI (p = 0.04). Serum zonulin inversely correlated with the standardized Mini-Mental State Examination (MMSE) score (p < 0.05), regardless of potential confounders. DISCUSSION: We found increased serum zonulin levels in patients with aMCI, LOAD and MIXED dementia, but not in VAD; moreover, zonulin levels were higher in aMCI converting to AD compared with stable ones. CONCLUSIONS: Our findings suggest that a dysregulation of intestinal-epithelial barrier and/or BBB may be an early specific event in AD-related neurodegeneration.
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Doença de Alzheimer , Disfunção Cognitiva , Demência Vascular , Humanos , Idoso , Doença de Alzheimer/diagnóstico , Haptoglobinas , Precursores de Proteínas , Disfunção Cognitiva/diagnósticoRESUMO
Cancer cells overexpress IF1, the endogenous protein that inhibits the hydrolytic activity of ATP synthase when mitochondrial membrane potential (ΔµH+) falls, as in ischemia. Other roles have been ascribed to IF1, but the associated molecular mechanisms are still under debate. We investigated the ability of IF1 to promote survival and proliferation in osteosarcoma and colon carcinoma cells exposed to conditions mimicking ischemia and reperfusion, as occurs in vivo, particularly in solid tumors. IF1-silenced and parental cells were exposed to the FCCP uncoupler to collapse ΔµH+ and the bioenergetics of cell models were validated. All the uncoupled cells preserved mitochondrial mass, but the implemented mechanisms differed in IF1-expressing and IF1-silenced cells. Indeed, the membrane potential collapse and the energy charge preservation allowed an increase in both mitophagy and mitochondrial biogenesis in IF1-expressing cells only. Interestingly, the presence of IF1 also conferred a proliferative advantage to cells highly dependent on oxidative phosphorylation when the uncoupler was washed out, mimicking cell re-oxygenation. Overall, our results indicate that IF1, by allowing energy preservation and promoting mitochondrial renewal, can favor proliferation of anoxic cells and tumor growth. Therefore, hindering the action of IF1 may be promising for the therapy of tumors that rely on oxidative phosphorylation for energy production.
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Neoplasias Ósseas , Osteossarcoma , Humanos , Mitocôndrias/metabolismo , Hipóxia/metabolismo , Osteossarcoma/metabolismo , Neoplasias Ósseas/metabolismo , Isquemia/metabolismo , Proliferação de Células , Trifosfato de Adenosina/metabolismoRESUMO
Sepsis is a time-dependent and life-threating condition related to macro- and micro-circulatory impairment leading to anaerobic metabolism and lactate increase. We assessed the prognostic accuracy of capillary lactates (CLs) vs. serum ones (SLs) on 48-h and 7-day mortality in patients with suspected sepsis. This observational, prospective, single-centre study was conducted between October 2021 and May 2022. Inclusion criteria were: (i) suspect of infection; (ii) qSOFA ≥ 2; (iii) age ≥ 18 years; (iv) signed informed consent. CLs were assessed with LactateProTM2®. 203 patients were included: 19 (9.3%) died within 48 h from admission to the Emergency Department, while 28 (13.8%) within 7 days. Patients deceased within 48 h (vs. survived) had higher CLs (19.3 vs. 5 mmol/L, p < 0.001) and SLs (6.5 vs. 1.1 mmol/L, p = 0.001). The best CLs predictive cut-off for 48-h mortality was 16.8 mmol/L (72.22% sensitivity, 94.02% specificity). Patients within 7 days had higher CLs (11.5 vs. 5 mmol/L, p = 0.020) than SLs (2.75 vs. 1.1 mmol/L, p < 0.001). The multivariate analysis confirmed CLs and SLs as independent predictors of 48-h and 7-day mortality. CLs can be a reliable tool for their inexpensiveness, rapidity and reliability in identifying septic patients at high risk of short-term mortality.
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Sepse , Choque Séptico , Humanos , Adolescente , Estudos Prospectivos , Reprodutibilidade dos Testes , Estudos Retrospectivos , Ácido Láctico , Serviço Hospitalar de EmergênciaRESUMO
Opioids such as morphine-acting at the mu opioid receptor-are the mainstay for treatment of moderate to severe pain and have good efficacy in these indications. However, these drugs produce a plethora of unwanted adverse effects including respiratory depression, constipation, immune suppression and with prolonged treatment, tolerance, dependence and abuse liability. Studies in ß-arrestin 2 gene knockout (ßarr2(-/-)) animals indicate that morphine analgesia is potentiated while side effects are reduced, suggesting that drugs biased away from arrestin may manifest with a reduced-side-effect profile. However, there is controversy in this area with improvement of morphine-induced constipation and reduced respiratory effects in ßarr2(-/-) mice. Moreover, studies performed with mice genetically engineered with G-protein-biased mu receptors suggested increased sensitivity of these animals to both analgesic actions and side effects of opioid drugs. Several new molecules have been identified as mu receptor G-protein-biased agonists, including oliceridine (TRV130), PZM21 and SR-17018. These compounds have provided preclinical data with apparent support for bias toward G proteins and the genetic premise of effective and safer analgesics. There are clinical data for oliceridine that have been very recently approved for short term intravenous use in hospitals and other controlled settings. While these data are compelling and provide a potential new pathway-based target for drug discovery, a simpler explanation for the behavior of these biased agonists revolves around differences in intrinsic activity. A highly detailed study comparing oliceridine, PZM21 and SR-17018 (among others) in a range of assays showed that these molecules behave as partial agonists. Moreover, there was a correlation between their therapeutic indices and their efficacies, but not their bias factors. If there is amplification of G-protein, but not arrestin pathways, then agonists with reduced efficacy would show high levels of activity at G-protein and low or absent activity at arrestin; offering analgesia with reduced side effects or 'apparent bias'. Overall, the current data suggests-and we support-caution in ascribing biased agonism to reduced-side-effect profiles for mu-agonist analgesics.
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Analgésicos Opioides , Aprovação de Drogas , Dor/tratamento farmacológico , Analgésicos Opioides/química , Analgésicos Opioides/uso terapêutico , Animais , Avaliação Pré-Clínica de Medicamentos , Humanos , Camundongos , Camundongos Knockout , Dor/genética , Dor/metabolismo , Dor/patologia , beta-Arrestina 2/agonistas , beta-Arrestina 2/genética , beta-Arrestina 2/metabolismoRESUMO
Familial aggregation is a significant risk factor for the development of thyroid cancer and familial non-medullary thyroid cancer (FNMTC) accounts for 5-7% of all NMTC. Whole exome sequencing analysis in the family affected by FNMTC with oncocytic features where our group previously identified a predisposing locus on chromosome 19p13.2, revealed a novel heterozygous mutation (c.400G > A, NM_012335; p.Gly134Ser) in exon 5 of MYO1F, mapping to the linkage locus. In the thyroid FRTL-5 cell model stably expressing the mutant MYO1F p.Gly134Ser protein, we observed an altered mitochondrial network, with increased mitochondrial mass and a significant increase in both intracellular and extracellular reactive oxygen species, compared to cells expressing the wild-type (wt) protein or carrying the empty vector. The mutation conferred a significant advantage in colony formation, invasion and anchorage-independent growth. These data were corroborated by in vivo studies in zebrafish, since we demonstrated that the mutant MYO1F p.Gly134Ser, when overexpressed, can induce proliferation in whole vertebrate embryos, compared to the wt one. MYO1F screening in additional 192 FNMTC families identified another variant in exon 7, which leads to exon skipping, and is predicted to alter the ATP-binding domain in MYO1F. Our study identified for the first time a role for MYO1F in NMTC.
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Proliferação de Células , Embrião não Mamífero/patologia , Mitocôndrias/patologia , Mutação , Miosina Tipo I/genética , Câncer Papilífero da Tireoide/patologia , Neoplasias da Glândula Tireoide/patologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Apoptose , Células Cultivadas , Criança , Cromossomos Humanos Par 19 , Embrião não Mamífero/metabolismo , Feminino , Predisposição Genética para Doença , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Mitocôndrias/genética , Mitocôndrias/metabolismo , Miosina Tipo I/química , Miosina Tipo I/metabolismo , Consumo de Oxigênio , Linhagem , Conformação Proteica , Câncer Papilífero da Tireoide/genética , Câncer Papilífero da Tireoide/metabolismo , Neoplasias da Glândula Tireoide/genética , Neoplasias da Glândula Tireoide/metabolismo , Adulto Jovem , Peixe-ZebraRESUMO
Alcohol consumption can cause, beyond addiction, roughly 200 different diseases and at least fourteen types of cancer. In 2016 the WHO estimated that 29% of alcohol-related deaths were mainly due to oncological diseases, liver cirrhosis (20%), and cardiovascular disorders (19%). The aim of this review was to focus on the absorption and metabolism of ethanol and discuss the main conditions caused by alcohol consumption (i.e., liver and cardiovascular diseases, and tumors). This narrative review is based on a detailed analysis of the scientific literature published before January 31, 2024 (PubMed, Web of Science, Scopus, Google Scholar). Approximately 90% of the absorbed alcohol reaches the liver where it is metabolized to acetaldehyde, a highly reactive and toxic compound. The excessive use of alcohol causes damage to several organs and systems, mainly the liver (e.g., steatosis, steato-hepatitis, fibrosis, and cirrhosis), cardiovascular system (cardiomyopathy, arrythmias, arterial hypertension, and stroke), and significantly contribute to the onset of neoplastic lesions to various organs including the esophagus, liver and breast. Even moderate drinking appears not to reduce mortality risk. Alcohol intake is one of the main risk factors for several pathological conditions and social problems, thus drastically impacting on public health. Proper awareness of the high risk related to alcohol consumption is of crucial importance to reduce the harm to public health.
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Since the rise of awareness of gluten/wheat-related disorders in the academic and clinical field in the last few decades, misinformation regarding the gluten-free diet (GFD) and its impact on health has been spreading among the general population. Despite the established link between gluten and celiac disease (CD), where a GFD is mandatory to reach clinical and histological remission, things are more complicated when it comes to non-celiac gluten/wheat sensitivity (NCGWS) and other autoimmune/dysimmune disorders. In the last conditions, a beneficial effect of gluten withdrawal has not been properly assessed, but still is often suggested without strong supporting evidence. In this context, women have always been exposed, more than men, to higher social pressure related to nutritional behaviors and greater engagement in controlling body weight. With this narrative review, we aim to summarize current evidence on the adherence to a GFD, with particular attention to the impact on women's health.
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Doença Celíaca , Glutens , Masculino , Humanos , Feminino , Glutens/efeitos adversos , Dieta Livre de Glúten , Peso Corporal , Saúde da MulherRESUMO
BACKGROUND: Celiac disease (CD) is an autoimmune disorder triggered by gluten ingestion. Herein, we assessed clinical, serological and histopathological findings of a single-center, large cohort of CD patients diagnosed and followed-up over forty years. METHODS: From January 1980 to December 2020, 1547 CD patients (1170 females; age range: 8-81 years; F:M ratio = 3.1:1) were diagnosed in an Italian tertiary referral center. Comorbidities and complications were recorded at diagnosis and during follow-up. RESULTS: CD diagnoses quadrupled after 2000. The most frequent phenotype was the non-classical CD (63.3%), and the most prevalent histotype was Marsh 3C (44.7%). Gastrointestinal manifestations, detectable in 51% of patients, were diarrhea (24.3%), bloating (28%) and aphthous stomatitis (19.7%). The most common CD-associated disorder was osteopenia (59.9%), predominant in females (64.3%); extraintestinal manifestations included anemia (35.8% iron-deficiency; 87% folic acid malabsorption), cryptogenic hypertransaminasemia (27.9%), and recurrent miscarriages (11.5%). Thyroiditis (26.9%), type 1 diabetes mellitus (2.9%), and dermatitis herpetiformis (1.4%) were the most common CD-related autoimmune disorders. Six patients had inflammatory bowel disease. Complications and mortality rate occurred in 1.8% and 1.9%, respectively. CONCLUSIONS: This single-center, large cohort analysis confirmed that CD presentation changed over the years, with an increase of non-classical and subclinical clinical phenotypes.
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Doença Celíaca , Humanos , Doença Celíaca/epidemiologia , Feminino , Masculino , Criança , Itália/epidemiologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Pessoa de Meia-Idade , Adulto Jovem , Centros de Atenção Terciária/estatística & dados numéricos , ComorbidadeRESUMO
INTRODUCTION: During the treatment of alcohol use disorder, alcohol withdrawal syndrome (AWS) can occur. Benzodiazepines remain the "gold standard" for the pharmacological treatment of AWS. However, other drugs have been approved in some European Countries for the treatment of AWS: namely, clomethiazole in Spain and Germany and sodium oxybate in Italy and Austria. Acute alcohol-associated hepatitis (AAH) is a distinct clinical syndrome characterized by the recent onset of jaundice with or without other signs of liver decompensation in patients with ongoing alcohol consumption. RATIONALE: We report 4 paradigmatic clinical cases to analyze the efficacy, safety, and tolerability of the very short half-life (30-45 minutes) sodium oxybate (SO) in the management of AWS with moderate to severe AAH. Compared to SO, "as needed" short-acting benzodiazepines, currently prescribed to treat AWS in patients with AAH, have a much longer half-life (5-25 hours) which increases the risk of drug accumulation. The very short half-life of SO provides a fixed dose approach allowing for a more effective control of AWS than "as needed" therapy throughout the 24 hours. PATIENT CONCERNS: Patients reported anxiety, agitation, diffuse abdominal pain, loss of appetite, and nausea with elevation in serum bilirubin and 2 of them had abdomen distension due to ascites. DIAGNOSIS: Patients were affected by moderate or severe AWS and moderate or severe AAH on alcohol-related liver cirrhosis. INTERVENTIONS: In order to suppress AWS, all patients were treated with oral sodium oxybate at a dose of 25 mg/kg/day, progressively increased to 50 to 100 mg/kg/day, divided into 3 to 5 administrations. OUTCOMES: SO was efficient, safe and tolerable in suppressing AWS even in patients with severe AAH. All treated patients showed a rapid improvement of all symptom (via the Clinical Institute of Withdrawal Assessment for Alcohol Scale) and liver test scores (Model for End-Stage Liver Disease). CONCLUSION: Because of its short half-life, SO can be considered a safe and effective pharmacological option for the AWS in patients with moderate to severe AAH even in comparison to short-acting benzodiazepines, thus avoiding the risk of accumulation. Notably, SO guarantees a fixed approach to cover the possible onset of AWS throughout the 24 hours.
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Hepatite Alcoólica , Oxibato de Sódio , Síndrome de Abstinência a Substâncias , Humanos , Masculino , Síndrome de Abstinência a Substâncias/tratamento farmacológico , Síndrome de Abstinência a Substâncias/etiologia , Hepatite Alcoólica/tratamento farmacológico , Hepatite Alcoólica/complicações , Oxibato de Sódio/uso terapêutico , Oxibato de Sódio/efeitos adversos , Pessoa de Meia-Idade , Adulto , FemininoRESUMO
INTRODUCTION: Worldwide, almost 1.2 million people drive under the influence of alcohol. However, early identification of alcohol use disorder (AUD) in subjects driving under the influence (DUI) of alcohol is seldom achieved. AIM: The aim of our retrospective study is to investigate the presence of AUD in a population of DUI subjects who had their driving license suspended, and if they were following a specific rehabilitation program. METHODS AND RESULTS: 750 subjects were retrospectively enrolled from 2018 to 2021. DSM-V to assess AUD was used. Forty-eight (6.4%) subjects presented a diagnosis of AUD, after one month they showed a statistically significant reduction of carbohydrate-deficient transferrin (CDT) (p<0.0001); however, none were following a program for the treatment of AUD. CONCLUSIONS: This outpatient setting may be considered a place of primary and secondary prevention where DUI subjects with a diagnosis of AUD may be entrusted to a Centre in order to follow rehabilitation treatment.
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Alcoolismo , Dirigir sob a Influência , Humanos , Estudos Retrospectivos , Itália/epidemiologia , Masculino , Feminino , Alcoolismo/epidemiologia , Adulto , Pessoa de Meia-Idade , Dirigir sob a Influência/estatística & dados numéricos , Pacientes Ambulatoriais , Transferrina/análise , Transferrina/metabolismo , Transferrina/análogos & derivados , Diagnóstico Precoce , Idoso , Condução de VeículoRESUMO
Alcoholic liver disease (ALD) is currently, worldwide, the second most common cause of human fatalities every year. Alcohol use disorders (AUDs) lead to 80% of hepatotoxic deaths, and about 40% of cases of cirrhosis are alcohol-related. An acceptable daily intake (ADI) of ethanol is hard to establish and studies somewhat controversially recommend a variety of dosages of ADI, whilst others regard any intake as dangerous. Steatohepatitis should be viewed as "the rate limiting step": generally, it can be overcome by abstinence, although in some patients, abstinence has little effect, with the risk of fibrosis, leading in some cases to hepatocellular carcinoma (HCC). Chronic alcoholism can also cause hypercortisolism, specifically pseudo-Cushing Syndrome, whose diagnosis is challenging. If fibrosis is spotted early, patients may be enrolled in detoxification programs to achieve abstinence. Treatment drugs include silybin, metadoxine and adenosyl methionine. Nutrition and the proper use of micronutrients are important, albeit often overlooked in ALD treatment. Other drugs, with promising antifibrotic effects, are now being studied. This review deals with the clinical and pathogenetic aspects of alcohol-related liver fibrosis and suggests possible future strategies to prevent cirrhosis.
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Alcoolismo , Humanos , Alcoolismo/complicações , Cirrose Hepática/etiologia , Cirrose Hepática Alcoólica/complicações , Cirrose Hepática Alcoólica/etiologia , Hepatopatias Alcoólicas/etiologia , Hepatopatias Alcoólicas/complicaçõesRESUMO
BACKGROUND: Botulinum toxin is an effective therapeutic option for chronic anal fissure. However, there is no evidence about treatment standardization and long-term follow-up. We aimed to evaluate the short- and long-term efficacy and safety of botulinum toxin compared to close lateral internal sphincterotomy, with a 5-year follow-up. METHODS: This was a prospective, controlled, single-center study conducted at University Hospital of Ferrara, Ferrara, Italy. The primary outcome was fissure healing at 1 month. Secondary outcomes were Quality-of-Life (QoL) at 1 month and after 5 years, and fissure recurrence at 6 months and 5 years. RESULTS: A total of 59 patients received botulinum toxin injection (Botox), and 32 underwent lateral internal sphincterotomy. At 1 month after treatments, postoperative pain decreased faster and significantly more in the Botox group (30 vs. 60 mm; P<0.001); fissure re-epithelization was observed in 59.4% of the surgical group compared to 25.4% of Botox (P=0.0001). Anal sphincter pressures decreased more in surgical group (P=0.044), although severe anal incontinence was present only in this subset (6.2%; P=0.041). Compared to surgery, patients who received Botox had higher satisfaction rates (P<0.001). Fissure recurrence at 6 months was more common in Botox than surgical group (16.9% vs. 3.2%, respectively; P=0.053). The overall healing rate improved in all patients and persisted at 12 months and 5 years in both groups with overall high patient satisfaction despite mild anal incontinence in 21.8% in the surgery group (P<0.05). CONCLUSIONS: Botox, rather than surgery, should be considered the first-line treatment for chronic anal fissure.
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Toxinas Botulínicas Tipo A , Fissura Anal , Humanos , Fissura Anal/tratamento farmacológico , Fissura Anal/cirurgia , Estudos Prospectivos , Feminino , Masculino , Doença Crônica , Toxinas Botulínicas Tipo A/administração & dosagem , Toxinas Botulínicas Tipo A/uso terapêutico , Pessoa de Meia-Idade , Seguimentos , Adulto , Resultado do Tratamento , Qualidade de Vida , Fármacos Neuromusculares/uso terapêutico , Fármacos Neuromusculares/administração & dosagem , Recidiva , Esfincterotomia Lateral Interna , Fatores de Tempo , Canal Anal/cirurgiaRESUMO
BACKGROUND & AIMS: Although chronic diarrhea and constipation are common, the treatment is symptomatic because their pathophysiology is poorly understood. Accumulating evidence suggests that the microbiota modulates gut function, but the underlying mechanisms are unknown. We therefore investigated the pathways by which microbiota modulates gastrointestinal motility in different sections of the alimentary tract. METHODS: Gastric emptying, intestinal transit, muscle contractility, acetylcholine release, gene expression, and vasoactive intestinal polypeptide (VIP) immunoreactivity were assessed in wild-type and Myd88-/-Trif-/- mice in germ-free, gnotobiotic, and specific pathogen-free conditions. Effects of transient colonization and antimicrobials as well as immune cell blockade were investigated. VIP levels were assessed in human full-thickness biopsies by Western blot. RESULTS: Germ-free mice had similar gastric emptying but slower intestinal transit compared with specific pathogen-free mice or mice monocolonized with Lactobacillus rhamnosus or Escherichia coli, the latter having stronger effects. Although muscle contractility was unaffected, its neural control was modulated by microbiota by up-regulating jejunal VIP, which co-localized with and controlled cholinergic nerve function. This process was responsive to changes in the microbial composition and load and mediated through toll-like receptor signaling, with enteric glia cells playing a key role. Jejunal VIP was lower in patients with chronic intestinal pseudo-obstruction compared with control subjects. CONCLUSIONS: Microbial control of gastrointestinal motility is both region- and bacteria-specific; it reacts to environmental changes and is mediated by innate immunity-neural system interactions. By regulating cholinergic nerves, small intestinal VIP plays a key role in this process, thus providing a new therapeutic target for patients with motility disorders.
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Motilidade Gastrointestinal , Peptídeo Intestinal Vasoativo , Humanos , Camundongos , Animais , Peptídeo Intestinal Vasoativo/metabolismo , Motilidade Gastrointestinal/fisiologia , Neuroglia/metabolismo , ColinérgicosRESUMO
Systemic inflammation and neuroinflammation affect the natural course of the sporadic form of Alzheimer's disease (AD), as supported by epidemiological and preclinical data, and several epidemiological studies indicate a higher prevalence of AD in patients with inflammatory bowel disease. In this study, we explored whether colitis induced by dextran sulfate sodium (DSS) in young, presymptomatic/preplaque mice worsens and/or anticipates age-dependent cognitive impairment in Tg2576, a widely used mouse model of AD. We demonstrated that DSS colitis induced in young Tg2576 mice anticipates the onset age of learning and memory deficit in the Morris water maze test. To explore potential mechanisms behind the acceleration of cognitive decline in Tg2576 mice by DSS colitis, we focused on gut microbiota, systemic inflammation and neuroinflammation markers. We observed a Firmicutes/Bacteroidetes ratio change in Tg2576 DSS animals comparable to that of elderly Tg2576 mice, suggesting accelerated microbiota aging in Tg2576 DSS mice, a change not observed in C57BL6 DSS mice. We also observed substantial differences between Tg2576 and WT mice in several inflammation and neuroinflammation-related parameters as early as 3 months of age, well before plaque deposition, a picture which evolved rapidly (between 3 and 5.5 months of age) in contrast to Tg2576 and WT littermates not treated with DSS. In detail, following induction of DSS colitis, WT and Tg2576 mice exhibited contrasting features in the expression level of inflammation-evoked astrocyte-associated genes in the hippocampus. No changes in microglial features occurred in the hippocampus between the experimental groups, whereas a reduced glial fibrillary acidic protein immunoreactivity was observed in Tg2576 vs. WT mice. This finding may reflect an atrophic, "loss-of-function" profile, further exacerbated by DSS where a decreased of GFAP mRNA expression level was detected. In conclusion, we suggest that as-yet unidentified peripheral mediators evoked by DSS colitis and involving the gut-brain axis emphasize an astrocyte "loss-of-function" profile present in young Tg2576 mice, leading to impaired synaptic morphological and functional integrity as a very early sign of AD.
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Doença de Alzheimer , Colite , Sulfato de Dextrana , Modelos Animais de Doenças , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Animais , Doença de Alzheimer/patologia , Doença de Alzheimer/genética , Camundongos , Colite/induzido quimicamente , Colite/patologia , Sulfato de Dextrana/toxicidade , Microbioma Gastrointestinal , Fenótipo , Masculino , Hipocampo/patologia , Hipocampo/metabolismo , Feminino , Disfunção Cognitiva/genética , Disfunção Cognitiva/patologia , Disfunção Cognitiva/etiologiaRESUMO
Introduction: The accurate distinction between periprosthetic joint infections (PJI) and aseptic failures (AF) is of paramount importance due to differences in treatment. However, this could be challenging by using the current criteria. Various synovial fluid biomarkers are being assessed to improve the diagnostic accuracy. Myeloperoxidase (MPO), an enzyme contained in the granules of neutrophils, may be a promising biomarker for PJI. Methods: Synovial fluids of 99 patients (n = 65 PJI according to EBJIS criteria; n = 34 AF) were collected in two specialized orthopedic centers. PJI were divided into acute (n = 33) and low-grade (n = 32) according to previously published classification. An activity assay specific for active MPO was performed in each sample. Ability of MPO to correctly discriminate patients with PJI from AF was determined by ROC analysis. The best discriminating cut-off value was determined by calculating the J Youden index. For all analyses, a P value < 0.05 was considered statistically significant. Results: Active MPO was higher in PJI than AF (P < 0.0001). The ROC analysis revealed a significant area under the curve (AUC: 0.86; 95% CI: 0.78-0.93, P < 0.0001). A cut-off value of 561.9 U/mL, with good sensitivity (0.69) and specificity (0.88), discriminated between AF and PJI (accuracy 75.76%, 95% CI: 66.11-83.81%, positive likelihood ratio 5.88, 95% CI: 2.31-14.98 and negative likelihood ratio 0.35, 95%CI: 0.24-0.51). No difference in MPO levels was found between acute and chronic low-grade PJI. Conclusion: The proposed assay appears to be a reliable and affordable tool for detecting the active MPO in synovial fluid, with promising characteristics of sensitivity and specificity in discriminating both acute and low-grade PJI from AF. Further studies are needed to confirm MPO diagnostic cut-off values and validate their use in the routine clinical practice.
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Sex and gender are fundamental health determinants and their role as modifiers of treatment response is increasingly recognized. Norepinephrine is a cornerstone of septic shock management and its use is based on the highest level of evidence compared to dopamine. The related 2021 Surviving Sepsis Campaign (SCC) recommendation is presumably applicable to both females and males; however, a sex- and gender-based analysis is lacking, thus not allowing generalizable conclusions. This paper was aimed at exploring whether sex- and gender-disaggregated data are available in the evidence supporting this recommendation. For all the studies underpinning it, four pairs of authors, including a woman and a man, extracted data concerning sex and gender, according to the Sex and Gender Equity in Research guidelines. Nine manuscripts were included with an overall population of 2126 patients, of which 43.2% were females. No sex analysis was performed and gender was never reported. In conclusion, the present manuscript highlighted that the clinical studies underlying the SCC recommendation of NE administration in septic shock have neglected the likely role of sex and gender as modifiers of treatment response, thus missing the opportunity of sex- and gender-specific guidelines.
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Background: Chronic constipation (CC) is a severe symptom in Parkinson's disease (PD), with an unclear pathogenesis. Abnormalities of the enteric nervous system (ENS) and/or intestinal epithelial barrier (IEB) may be pathophysiologically relevant in PD patients with CC. We investigated possible molecular changes of the IEB in PD/CCs compared with CCs and controls. Methods: Twelve PD/CCs (2 female, age range 51-80 years), 20 CCs (15 female, age range 27-78 years), and 23 controls (11 female, age range 32-74 years) were enrolled. Ten PD/CCs and 10 CCs were functionally characterized by anorectal manometry (AM) and transit time (TT). Colon biopsies were obtained and assessed for gene and protein expression, and localization of IEB tight junction markers claudin-4 (CLDN4), occludin-1 (OCCL-1), and zonula occludens-1 (ZO-1) by RT-qPCR, immunoblot and immunofluorescence labeling. Results: PD/CCs were clustered in 2 functional categories: patients with delayed TT and altered AM (60%), and a second group showing only modifications in AM pattern (40%). Gene expression of CLDN4, OCCL-1 and ZO-1 was higher in PD/CCs than controls (P<0.05). Conversely, PD/CCs showed a trend to decrease (P>0.05) in CLDN4 and OCCL-1 protein levels than controls, whereas ZO-1 protein was comparable. In PD/CCs compared with controls, decreasing tendency of vasoactive intestinal polypeptide mRNA, protein and immunoreactive fiber density were observed, although the difference was not statistically significant. Conclusion: Transit and anorectal dysfunctions in PD/CCs are associated with difference in ZO-1, OCCL-1 and CLDN4 expression, thus supporting the role of an altered IEB as a contributory mechanism to possible neuronal abnormalities.
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Celiac disease (CD) is an autoimmune disorder caused by gluten ingestion in genetically predisposed individuals. In addition to the typical gastrointestinal symptoms (e.g., diarrhea, bloating, and chronic abdominal pain), CD may also present with a broad spectrum of manifestations, including low bone mineral density (BMD) and osteoporosis. The etiopathology of bone lesions in CD is multifactorial and other conditions, rather than mineral and vitamin D malabsorption, may affect skeletal health, especially those related to the endocrine system. Here, we describe CD-induced osteoporosis in an attempt to enlighten new and less-known aspects, such as the influence of the intestinal microbiome and sex-related differences on bone health. This review describes the role of CD in the development of skeletal alterations to provide physicians with an updated overview on this debated topic and to improve the management of osteoporosis in CD.