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Late-onset Pompe Disease (LOPD) is a rare genetic disorder caused by the deficiency of acid alpha-glucosidase leading to progressive cellular dysfunction due to the accumulation of glycogen in the lysosome. The mechanism of relentless muscle damage - a classic manifestation of the disease - has been extensively studied by analysing the whole muscle tissue; however, little, if any, is known about transcriptional heterogeneity among nuclei within the multinucleated skeletal muscle cells. This is the first report of application of single nuclei RNA sequencing to uncover changes in the gene expression profile in muscle biopsies from eight patients with LOPD and four muscle samples from age and gender matched healthy controls. We matched these changes with histology findings using GeoMx Spatial Transcriptomics to compare the transcriptome of control myofibers from healthy individuals with non-vacuolated (histologically unaffected) and vacuolated (histologically affected) myofibers of LODP patients. We observed an increase in the proportion of slow and regenerative muscle fibers and macrophages in LOPD muscles. The expression of the genes involved in glycolysis was reduced, whereas the expression of the genes involved in the metabolism of lipids and amino acids was increased in non-vacuolated fibers, indicating early metabolic abnormalities. Additionally, we detected upregulation of autophagy genes, and downregulation of the genes involved in ribosomal and mitochondrial function leading to defective oxidative phosphorylation. The upregulation of the genes associated with inflammation, apoptosis and muscle regeneration was observed only in vacuolated fibers. Notably, enzyme replacement therapy - the only available therapy for the disease - showed a tendency to restore metabolism dysregulation, particularly within slow fibers. A combination of single nuclei RNA sequencing and spatial transcriptomics revealed the landscape of normal and the diseased muscle, and highlighted the early abnormalities associated with the disease progression. Thus, the application of these two new cutting-edge technologies provided insight into the molecular pathophysiology of muscle damage in LOPD and identified potential avenues for therapeutic intervention.
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BACKGROUND & AIMS: The impact of patient sex on the presentation of inflammatory bowel disease (IBD) has been poorly evaluated. Our aims were to assess potential disparities in IBD phenotype and progression between sexes. METHODS: We performed an observational multicenter study that included patients with Crohn's disease (CD) or ulcerative colitis from the Spanish ENEIDA registry. Data extraction was conducted in July 2021. RESULTS: A total of 51,595 patients with IBD were included, 52% were males and 25,947 had CD. The median follow-up period after diagnosis was 9 years in males and 10 years in females. In CD, female sex was an independent risk factor for medium disease onset (age, 17-40 y) (relative risk ratio, 1.45; 95% CI, 1.31-1.62), later disease onset (age, >40 y) (relative risk ratio, 1.55; 95% CI, 1.38-1.73), exclusive colonic involvement (odds ratio, 1.24; 95% CI, 1.14-1.34), inflammatory behavior (odds ratio, 1.14; 95% CI, 1.07-1.21), and extraintestinal manifestations (odds ratio, 1.48; 95% CI, 1.38-1.59). However, female sex was a protective factor for upper gastrointestinal involvement (odds ratio, 0.84; 95% CI, 0.79-0.90), penetrating behavior (odds ratio, 0.76; 95% CI, 0.70-0.82), perianal disease (odds ratio, 0.77; 95% CI, 0.71-0.82), and complications (odds ratio, 0.73; 95% CI, 0.66-0.80). In ulcerative colitis, female sex was an independent risk factor for extraintestinal manifestations (odds ratio, 1.48; 95% CI, 1.26-1.61). However, female sex was an independent protective factor for disease onset from age 40 onward (relative risk ratio, 0.76; 95% CI, 0.66-0.87), left-sided colonic involvement (relative risk ratio, 0.72; 95% CI, 0.67-0.78), extensive colonic involvement (relative risk ratio, 0.59; 95% CI, 0.55-0.64), and abdominal surgery (odds ratio, 0.78; 95% CI, 0.69-0.88). CONCLUSIONS: There is sexual dimorphism in IBD. The patient's sex should be taken into account in the clinical management of the disease.
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BACKGROUND AND AIMS: Familial inflammatory bowel disease (IBD) history is a controversial prognostic factor in IBD. We aimed to evaluate the impact of a familial history of IBD on the use of medical and surgical treatments in the biological era. METHODS: Patients included in the prospectively maintained ENEIDA database and diagnosed with IBD after 2005 were included. Familial forms were defined as those cases with at least one first-degree relative diagnosed with IBD. Disease phenotype, the use of biological agents, or surgical treatments were the main outcomes. RESULTS: A total of 5263 patients [2627 Crohn's disease (CD); 2636 ulcerative colitis (UC)] were included, with a median follow-up of 31 months. Of these, 507 (10%) corresponded to familial forms. No clinical differences were observed between familial and sporadic IBD forms except a lower age at IBD diagnosis and a higher rate of males in familial forms of UC. In CD, the proportions of patients treated with thiopurines (54.4% vs 46.7%; P = .015) and survival time free of thiopurines (P = .009) were lower in familial forms. No differences were found regarding the use of biological agents. Concerning surgery, a higher rate of intestinal resections was observed in sporadic CD (14.8% vs 9.9%, P = .027). No differences were observed in UC. CONCLUSIONS: In the era of biological therapies, familial and sporadic forms of IBD show similar phenotypes and are managed medically in a similar way; whether these is due to lack of phenotypical differences or an effect of biological therapies is uncertain. What is already known on this topic: IBD's etiopathogenesis points to an interaction between environmental and genetic factors, being familial history a controversial prognostic factor. Biological agents use and need for surgery regarding familial or sporadic forms of IBDs present conflicting results. What this study adds: Familial and sporadic forms of IBD have similar phenotypes and are managed medically and surgically in a similar way. How this study might affect research, practice or policy: Familial aggregation should not be considered a factor associated with more aggressive disease.
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AIM: To compare the impact of an unrestricted diet with a 3-day low-residue diet before colonoscopy on bowel preparation quality. METHODS: A randomized, multicenter, researcher-blinded, parallel-group feasibility trial was conducted to assess the efficacy of an unrestricted diet versus a 3-day low-residue diet for colonoscopy preparation. Participants, aged 50 to 69, were enrolled in a colorectal cancer screening program with no factors linked to poor bowel cleansing. The Boston Bowel Preparation Scale was used to evaluate colon preparation during intubation and withdrawal. Secondary outcomes included bowel exploration time, adenoma and polyp detection rates, and preparation and diet tolerability. The trial is registered under Clinical Trials (NCT04664543). RESULTS: One hundred and two individuals (mean age 59.3 ± 5.5 years, 40.1% female) were randomly assigned to each diet. All participants in both groups achieved adequate preparation (Boston scores ≥ 2 in each segment). Complete adherence to preparation was observed in the majority of participants in both groups. No significant differences were noted between groups in withdrawal or cecal intubation times, or in adenoma detection rates. The unrestricted diet was better tolerated than the 3-day low-residue diet (82.5% vs. 32.3%). Preparation assessed during intubation was adequate in 82.5% of the unrestricted diet group and in 90.3% of the 3-day low-residue diet group. CONCLUSIONS: It is feasible to test the impact of an unrestricted diet for adequate bowel preparation. Comparable cleansing results were achieved, but the unrestricted diet showed better tolerability.
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Colonoscopy (CS) is an invasive diagnostic and therapeutic technique, allowing the study of the colon. It is a safe and well tolerated procedure. However, CS is associated with an increased risk of adverse events, insufficient preparation and incomplete examinations in the elderly or frail patient (PEA/F). The objective of this position paper was to develop a set of recommendations on risk assessment, indications and special care required for CS in the PEA/F. It was drafted by a group of experts appointed by the SCD, SCGiG and CAMFiC that agreed on eight statements and recommendations, between them to recommend against performing CS in patients with advanced frailty, to indicate CS only if the benefits clearly outweigh the risks in moderate frailty and to avoid repeating CS in patients with a previous normal procedure. We also recommended against performing screening CS in patients with moderate or advanced frailty.
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Fragilidade , Humanos , Idoso , Fragilidade/diagnóstico , Idoso Fragilizado , Colonoscopia/métodos , Medição de RiscoRESUMO
BACKGROUND: Acute lower gastrointestinal bleeding (ALGIB) is a common cause of hospitalization. Recent guidelines recommend the use of prognostic scales for risk stratification. However, it remains unclear whether risk scores are more accurate than some simpler prognostic variables. OBJECTIVE: To compare the predictive values of haemoglobin alone and the Oakland score for predicting outcomes in ALGIB patients. DESIGN: Single-centre, retrospective study at a University Hospital. Data were extracted from the hospital's clinical records. The Oakland score was calculated at admission. Study outcomes were defined according to the original article describing the Oakland score: safe discharge (the primary Oakland score outcome), transfusion, rebleeding, readmission, therapeutic intervention and death. Area under the receiver operating characteristics (AUROC) curve and accuracy using haemoglobin and the Oakland score were calculated for each outcome. RESULTS: Two hundred and fifty-eight patients were included. Eighty-four (32.6%) needed transfusion, 50 (19.4%) presented rebleeding, 31 (12.1%) required therapeutic intervention, 20 (7.8%) were readmitted and six (2.3%) died. There were no differences in the AUROC curve values for haemoglobin versus the Oakland score with regard to safe discharge (0.82 (0.77-0.88) vs 0.80 (0.74-0.86), respectively) or to therapeutic intervention and death. Haemoglobin was significantly better for predicting transfusion and rebleeding, and the Oakland score was significantly better for predicting readmission. CONCLUSION: In our study, the Oakland score did not perform better than haemoglobin alone for predicting the outcome of patients with ALGIB. The usefulness of risk scores for predicting outcomes in clinical practice remains uncertain.
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Hemorragia Gastrointestinal , Hemoglobinas , Humanos , Hemorragia Gastrointestinal/etiologia , Hemorragia Gastrointestinal/diagnóstico , Hemorragia Gastrointestinal/mortalidade , Hemorragia Gastrointestinal/terapia , Hemoglobinas/análise , Masculino , Estudos Retrospectivos , Feminino , Idoso , Pessoa de Meia-Idade , Prognóstico , Transfusão de Sangue/estatística & dados numéricos , Medição de Risco , Readmissão do Paciente/estatística & dados numéricos , Valor Preditivo dos Testes , Recidiva , Curva ROC , Idoso de 80 Anos ou maisRESUMO
INTRODUCTION: The prevalence of penetrating complications in Crohn's disease (CD) increases progressively over time, but evidence on the medical treatment in this setting is limited. The aim of this study was to evaluate the effectiveness of biologic agents in CD complicated with internal fistulizing disease. METHODS: Adult patients with CD-related fistulae who received at least 1 biologic agent for this condition from the prospectively maintained ENEIDA registry were included. Exclusion criteria involved those receiving biologics for perianal disease, enterocutaneous, rectovaginal, anastomotic, or peristomal fistulae. The primary end point was fistula-related surgery. Predictive factors associated with surgery and fistula closure were evaluated by multivariate logistic regression and survival analyses. RESULTS: A total of 760 patients from 53 hospitals (673 receiving anti-tumor necrosis factors, 69 ustekinumab, and 18 vedolizumab) were included. After a median follow-up of 56 months (interquartile range, 26-102 months), 240 patients required surgery, with surgery rates of 32%, 41%, and 24% among those under anti-tumor necrosis factor, vedolizumab, or ustekinumab, respectively. Fistula closure was observed in 24% of patients. Older patients, ileocolonic disease, entero-urinary fistulae, or an intestinal stricture distal to the origin of the fistula were associated with a higher risk of surgery, whereas nonsmokers and combination therapy with an immunomodulator reduced this risk. DISCUSSION: Biologic therapy is beneficial in approximately three-quarters of patients with fistulizing CD, achieving fistula closure in 24%. However, around one-third still undergo surgery due to refractory disease. Some patient- and lesion-related factors can identify patients who will obtain more benefit from these drugs.
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Doença de Crohn , Fístula , Fístula Retal , Adulto , Humanos , Doença de Crohn/complicações , Doença de Crohn/tratamento farmacológico , Doença de Crohn/cirurgia , Ustekinumab/uso terapêutico , Resultado do Tratamento , Terapia Biológica , Necrose , Estudos Retrospectivos , Fístula Retal/etiologia , Fístula Retal/terapiaRESUMO
INTRODUCTION: The objective of this study was to assess the durability, short-term and long-term effectiveness, and safety of tofacitinib in ulcerative colitis (UC) in clinical practice. METHODS: This is a retrospective multicenter study including patients with UC who had received the first tofacitinib dose at least 8 weeks before the inclusion. Clinical effectiveness was based on partial Mayo score. RESULTS: A total of 408 patients were included. Of them, 184 (45%) withdrew tofacitinib during follow-up (mean = 18 months). The probability of maintaining tofacitinib was 67% at 6 m, 58% at 12 m, and 49% at 24 m. The main reason for tofacitinib withdrawal was primary nonresponse (44%). Older age at the start of tofacitinib and a higher severity of clinical activity were associated with tofacitinib withdrawal. The proportion of patients in remission was 38% at week 4, 45% at week 8, and 47% at week 16. Having moderate-to-severe vs mild disease activity at baseline and older age at tofacitinib start were associated with a lower and higher likelihood of remission at week 8, respectively. Of 171 patients in remission at week 8, 83 (49%) relapsed. The probability of maintaining response was 66% at 6 m and 54% at 12 m. There were 93 adverse events related to tofacitinib treatment (including 2 pulmonary thromboembolisms [in patients with risk factors] and 2 peripheral vascular thrombosis), and 29 led to tofacitinib discontinuation. DISCUSSION: Tofacitinib is effective in both short-term and long-term in patients with UC. The safety profile is similar to that previously reported.
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Colite Ulcerativa , Humanos , Colite Ulcerativa/tratamento farmacológico , Resultado do Tratamento , Indução de Remissão , Estudos RetrospectivosRESUMO
Late-onset Pompe disease (LOPD) is a rare genetic disorder produced by mutations in the GAA gene and is characterized by progressive muscle weakness. LOPD muscle biopsies show accumulation of glycogen along with the autophagic vacuoles associated with atrophic muscle fibers. The expression of molecules related to muscle fiber atrophy in muscle biopsies of LOPD patients was studied using immunofluorescence and real-time PCR. BCL2 and adenovirus E1B 19-kDa interacting protein 3 (BNIP3), a well-known atrogene, was identified as a potential mediator of muscle fiber atrophy in LOPD muscle biopsies. Vacuolated fibers in LOPD patient muscle biopsies were smaller than nonvacuolated fibers and expressed BNIP3. The current data suggested that BNIP3 expression is regulated by inhibition of the AKT-mammalian target of rapamycin pathway, leading to phosphorylation of Unc-51 like autophagy activating kinase 1 (ULK1) at Ser317 by AMP-activated protein kinase. Myoblasts and myotubes obtained from LOPD patients and age-matched controls were studied to confirm these results using different molecular techniques. Myotubes derived from LOPD patients were likewise smaller and expressed BNIP3. Conclusively, transfection of BNIP3 into control myotubes led to myotube atrophy. These findings suggest a cascade that starts with the inhibition of the AKT-mammalian target of rapamycin pathway and activation of BNIP3 expression, leading to progressive muscle fiber atrophy. These results open the door to potential new treatments targeting BNIP3 to reduce its deleterious effects on muscle fiber atrophy in Pompe disease.
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Doença de Depósito de Glicogênio Tipo II , Atrofia/patologia , Doença de Depósito de Glicogênio Tipo II/genética , Doença de Depósito de Glicogênio Tipo II/patologia , Humanos , Proteínas de Membrana/genética , Fibras Musculares Esqueléticas/metabolismo , Proteínas Proto-Oncogênicas , Proteínas Proto-Oncogênicas c-akt , Serina-Treonina Quinases TOR/metabolismoRESUMO
Sarcoglycanopathies include four subtypes of autosomal recessive limb-girdle muscular dystrophies (LGMDR3, LGMDR4, LGMDR5 and LGMDR6) that are caused, respectively, by mutations in the SGCA, SGCB, SGCG and SGCD genes. Delta-sarcoglycanopathy (LGMDR6) is the least frequent and is considered an ultra-rare disease. Our aim was to characterize the clinical and genetic spectrum of a large international cohort of LGMDR6 patients and to investigate whether or not genetic or protein expression data could predict a disease's severity. This is a retrospective study collecting demographic, genetic, clinical and histological data of patients with genetically confirmed LGMDR6 including protein expression data from muscle biopsies. We contacted 128 paediatric and adult neuromuscular units around the world that reviewed genetic data of patients with a clinical diagnosis of a neuromuscular disorder. We identified 30 patients with a confirmed diagnosis of LGMDR6 of which 23 patients were included in this study. Eighty-seven per cent of the patients had consanguineous parents. Ninety-one per cent of the patients were symptomatic at the time of the analysis. Proximal muscle weakness of the upper and lower limbs was the most common presenting symptom. Distal muscle weakness was observed early over the course of the disease in 56.5% of the patients. Cardiac involvement was reported in five patients (21.7%) and four patients (17.4%) required non-invasive ventilation. Sixty per cent of patients were wheelchair-bound since early teens (median age of 12.0 years). Patients with absent expression of the sarcoglycan complex on muscle biopsy had a significant earlier onset of symptoms and an earlier age of loss of ambulation compared to patients with residual protein expression. This study confirmed that delta-sarcoglycanopathy is an ultra-rare neuromuscular condition and described the clinical and molecular characteristics of the largest yet-reported collected cohort of patients. Our results showed that this is a very severe and quickly progressive disease characterized by generalized muscle weakness affecting predominantly proximal and distal muscles of the limbs. Similar to other forms of sarcoglycanopathies, the severity and rate of progressive weakness correlates inversely with the abundance of protein on muscle biopsy.
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Distrofia Muscular do Cíngulo dos Membros , Distrofias Musculares , Sarcoglicanopatias , Adulto , Criança , Humanos , Debilidade Muscular , Distrofias Musculares/genética , Distrofia Muscular do Cíngulo dos Membros/diagnóstico , Distrofia Muscular do Cíngulo dos Membros/genética , Estudos Retrospectivos , Sarcoglicanopatias/genética , Sarcoglicanas/genética , Sarcoglicanas/metabolismoRESUMO
SOURCE CITATION: Lembo A, Sultan S, Chang L, et al. AGA clinical practice guideline on the pharmacological management of irritable bowel syndrome with diarrhea. Gastroenterology. 2022;163:137-51. 35738725.
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Síndrome do Intestino Irritável , Humanos , Síndrome do Intestino Irritável/complicações , Síndrome do Intestino Irritável/tratamento farmacológico , Diarreia/tratamento farmacológicoRESUMO
SOURCE CITATION: Chang L, Sultan S, Lembo A, et al. AGA clinical practice guideline on the pharmacological management of irritable bowel syndrome with constipation. Gastroenterology. 2022;163:118-36. 35738724.
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Síndrome do Intestino Irritável , Humanos , Síndrome do Intestino Irritável/complicações , Síndrome do Intestino Irritável/tratamento farmacológico , Fármacos Gastrointestinais/uso terapêutico , Constipação Intestinal/tratamento farmacológicoRESUMO
BACKGROUND: Helicobacter pylori infection is the most important risk factor for gastric cancer (GC). Human gastric adenocarcinoma develops after long-term H. pylori infection via the Correa cascade. This carcinogenic pathway describes the progression from gastritis to atrophy, intestinal metaplasia (IM), dysplasia and GC. Patients with atrophy and intestinal metaplasia are considered to have precancerous lesions of GC (PLGC). H. pylori eradication and endoscopy surveillance are currently the only interventions for preventing GC. Better knowledge of the biology of human PLGC may help find stratification markers and contribute to better understanding of biological mechanisms. One way to achieve this is by using co-expression network analysis. Weighted gene co-expression network analysis (WGCNA) is often used to identify modules from co-expression networks and relate them to clinical traits. It also allows identification of driver genes that may be critical for PLGC. AIM: The purpose of this study was to identify co-expression modules and differential gene expression in dyspeptic patients at different stages of the Correa pathway. METHODS: We studied 96 gastric biopsies from 78 patients that were clinically classified as: non-active (n = 10) and chronic-active gastritis (n = 20), atrophy (n = 12), and IM (n = 36). Gene expression of coding RNAs was determined by microarrays and non-coding RNAs by RNA-seq. The WGCNA package was used for network construction, module detection, module preservation and hub and driver gene selection. RESULTS: WGCNA identified 20 modules for coding RNAs and 4 for each miRNA and small RNA class. Modules were associated with antrum and corpus gastric locations, chronic gastritis and IM. Notably, coding RNA modules correlated with the Correa cascade. One was associated with the presence of H. pylori. In three modules, the module eigengene (ME) gradually increased in the stages toward IM, while in three others the inverse relationship was found. One miRNA module was negatively correlated to IM and was used for a mRNA-miRNA integration analysis. WGCNA also uncovered driver genes. Driver genes show both high connectivity within a module and are significantly associated with clinical traits. Some of those genes have been previously involved in H. pylori carcinogenesis, but others are new. Lastly, using similar external transcriptomic data, we confirmed that the discovered mRNA modules were highly preserved. CONCLUSION: Our analysis captured co-expression modules that provide valuable information to understand the pathogenesis of the progression of PLGC.
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Gastrite , Infecções por Helicobacter , Helicobacter pylori , MicroRNAs , Neoplasias Gástricas , Humanos , Neoplasias Gástricas/genética , Neoplasias Gástricas/patologia , Infecções por Helicobacter/complicações , Infecções por Helicobacter/genética , Infecções por Helicobacter/epidemiologia , Mucosa Gástrica/patologia , Gastrite/complicações , Gastrite/epidemiologia , Gastrite/patologia , Atrofia/complicações , Atrofia/patologia , MicroRNAs/genética , Metaplasia/genética , Metaplasia/complicações , Metaplasia/patologia , RNA MensageiroRESUMO
The 21st century has brough us a paradigm shift regarding patients care: the conventional physician-focused model of care has now changed into a patient-centered mode that puts the patient at the center of his own healthcare. Establishing a non-prescriptive and collaborative therapeutic approach, empowering patients to make major decisions on their management, and strict respect to the patient's autonomy are the major drivers of this patient-centered care. Among other multiple collectives, this change has greatly impacted patients and physicians who deal with inflammatory bowel disease (IBD).
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Doenças Inflamatórias Intestinais , Pacientes , Humanos , Atenção à Saúde , Medidas de Resultados Relatados pelo Paciente , Doenças Inflamatórias Intestinais/terapiaRESUMO
INTRODUCTION: Peptic ulcer disease (PUD) is a common cause of hospitalization worldwide. We assessed temporal trends in hospitalization for PUD in 36 Organisation for Economic Co-operation and Development (OECD) countries since the turn of the 21st century. METHODS: The OECD database contains data on PUD-related hospital discharges and mortality for 36 countries between 2000 and 2019. Hospitalization rates for PUD were expressed as annual rates per 100,000 persons. Joinpoint regression models were used to calculate the average annual percent change (AAPC) with 95% confidence intervals (CIs) for each country, which were pooled using meta-analyses. The incidence of PUD was forecasted to 2021 using autoregressive integrated moving average and Poisson regression models. RESULTS: The overall median hospitalization rate was 42.4 with an interquartile range of 29.7-60.6 per 100,000 person-years. On average, hospitalization rates (AAPC = -3.9%; 95% CI: -4.4, -3.3) and morality rates (AAPC = -4.7%; 95% CI: -5.6, -3.8) for PUD have decreased from 2000 to 2019 globally. The forecasted incidence of PUD hospitalizations in 2021 ranged from 3.5 per 100,000 in Mexico to 92.1 per 100,000 in Lithuania. Across 36 countries in the OECD, 329,000 people are estimated to be hospitalized for PUD in 2021. DISCUSSION: PUD remains an important cause of hospitalization worldwide. Reassuringly, hospitalizations and mortality for PUD have consistently been falling in OECD countries in North America, Latin America, Europe, Asia, and Oceania. Identifying underlying factors driving these trends is essential to sustaining this downward momentum.
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Organização para a Cooperação e Desenvolvimento Econômico , Úlcera Péptica , Hospitalização , Humanos , Incidência , Alta do Paciente , Úlcera Péptica/epidemiologiaRESUMO
Skeletal muscle contains multiple cell types that work together to maintain tissue homeostasis. Among these, satellite cells (SC) and fibroadipogenic progenitors cells (FAPs) are the two main stem cell pools. Studies of these cells using animal models have shown the importance of interactions between these cells in repair of healthy muscle, and degeneration of dystrophic muscle. Due to the unavailability of fresh patient muscle biopsies, similar analysis of interactions between human FAPs and SCs is limited especially among the muscular dystrophy patients. To address this issue here we describe a method that allows the use of frozen human skeletal muscle biopsies to simultaneously isolate and grow SCs and FAPs from healthy or dystrophic patients. We show that while the purified SCs differentiate into mature myotubes, purified FAPs can differentiate into adipocytes or fibroblasts demonstrating their multipotency. We find that these FAPs can be immortalized and the immortalized FAPs (iFAPs) retain their multipotency. These approaches open the door for carrying out personalized analysis of patient FAPs and interactions with the SCs that lead to muscle loss.
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Biópsia , Separação Celular , Criopreservação , Músculo Esquelético/citologia , Músculo Esquelético/patologia , Células Satélites de Músculo Esquelético/citologia , Células Satélites de Músculo Esquelético/patologia , Adolescente , Adulto , Idoso , Diferenciação Celular , Feminino , Voluntários Saudáveis , Humanos , Masculino , Pessoa de Meia-Idade , Células-Tronco Multipotentes/citologia , Células-Tronco Multipotentes/patologia , Distrofia Muscular de Duchenne/patologia , Adulto JovemRESUMO
BACKGROUND: Oculopharyngeal muscular dystrophy (OPMD) is an autosomal dominant, late-onset myopathy characterized by ptosis, dysphagia, and progressive proximal limb muscle weakness. The disease is produced by a short expansion of the (GCN)n triplet in the PABPN1 gene. The size of expansion has been correlated to the disease onset and severity. We report the clinical features of a large cohort of OPMD patients harboring the (GCN)15 allele from the Canary Islands. METHODS: A retrospective observational study was performed analyzing the clinical, demographic, and genetic data of 123 OPMD patients. Clinical data from this cohort were compared with clinical data collected in a large European study including 139 OPMD patients. RESULTS: A total of 113 patients (94.2%) carried the (GCN)15 expanded PABN1 allele. Age of symptoms' onset was 45.1 years. The most frequent symptom at onset was ptosis (85.2%) followed by dysphagia (12%). The severity of the disease was milder in the Canary cohort compared to European patients as limb weakness (35.1% vs. 50.4%), the proportion of patients that require assistance for walking or use a wheelchair (9.3% vs. 27.4%), and needed of surgery because of severe dysphagia (4.6% vs. 22.8%) was higher in the European cohort. CONCLUSIONS: Nearly 95% of patients with OPMD from the Canary Islands harbored the (GCN)15 expanded allele supporting a potential founder effect. Disease progression seemed to be milder in the (GCN)15 OPMD Canary cohort than in other cohorts with shorter expansions suggesting that other factors, apart from the expansion size, could be involved in the progression of the disease.
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Transtornos de Deglutição , Distrofia Muscular Oculofaríngea , Estudos de Coortes , Transtornos de Deglutição/genética , Humanos , Pessoa de Meia-Idade , Debilidade Muscular/etiologia , Distrofia Muscular Oculofaríngea/diagnóstico , Distrofia Muscular Oculofaríngea/genética , Proteína I de Ligação a Poli(A)/genética , EspanhaRESUMO
Helicobacter pylori infection is very common in the Spanish population and represents the main cause of chronic gastritis, peptic ulcer, and gastric cancer. The last iteration of Spanish consensus guidelines on H. pylori infection was conducted in 2016. Recent changes in therapeutic schemes along with increasing supporting evidence were key for developing the V Spanish Consensus Conference (May 2021). Fourteen experts performed a systematic review of the scientific evidence and developed a series of recommendations that were subjected to an anonymous Delphi process of iterative voting. Scientific evidence and the strength of the recommendation were classified using GRADE guidelines. An eradication therapy, when prescribed empirically, is considered acceptable when it reliably achieves, or preferably surpass, 90% cure rates. Currently, only quadruple therapies (with or without bismuth) and generally lasting 14 days, accomplish this goal in first- and second-line therapies. A non-bismuth quadruple concomitant regimen (proton pump inhibitor, clarithromycin, amoxicillin, and metronidazole) or a quadruple bismuth-based combination (proton pump inhibitor, bismuth, tetracycline, and metronidazole), are recommended as first-line regimens. Rescue therapies after eradication failure and management of H. pylori infection in peptic ulcer disease were also reviewed.
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Infecções por Helicobacter , Helicobacter pylori , Úlcera Péptica , Amoxicilina/uso terapêutico , Antibacterianos/uso terapêutico , Bismuto/uso terapêutico , Claritromicina/uso terapêutico , Quimioterapia Combinada , Infecções por Helicobacter/complicações , Infecções por Helicobacter/tratamento farmacológico , Humanos , Metronidazol/uso terapêutico , Úlcera Péptica/complicações , Inibidores da Bomba de Prótons/uso terapêuticoRESUMO
Inflammatory bowel disease (IBD) is a chronic, relapsing noninfectious inflammatory condition of the intestinal tract with two main phenotypes, ulcerative colitis (UC) and Crohn's disease (CD), and globally increasing incidence and prevalence. Nearly 80% of the IBD patients with active disease and 50% of those with inactive disease suffer fatigue with significant impairment of their quality of life. Fatigue has been associated with multiple factors in IBD patients but, in most cases, no direct cause can be identified, and risk factors in clinically quiescent IBD are contradictory. Furthermore, as the assessment of fatigue is subjective, there is an unmet clinical need for fatigue biomarkers. In this explorative study, we analyzed the plasma lipidomic profiles of 47 quiescent UC and CD patients (23 fatigued, 24 nonfatigued) using ultraperformance liquid chromatography-time-of-flight mass spectrometry (UPLC-TOFMS). The results showed changes in lipids associated with fatigue and IBD. Significantly decreased levels of phosphatidylcholines, plasmanyls, sphingomyelins, lysophosphatidylcholines, phosphatidylethanolamines, phosphatidylinositols, phosphatidylserines, and eicosanoids were observed in patients with fatigue. Network and metabolic pathway analysis indicated a dysregulation of the arachidonic acid and glycerophospholipid metabolisms and the sphingolipid pathway. The protein-metabolite interaction network showed interactions between functionally related metabolites and proteins, displaying 40 disease-associated hidden proteins including ABDH4, GLTP, and LCAT.
Assuntos
Colite Ulcerativa , Doenças Inflamatórias Intestinais , Fadiga , Humanos , Lipidômica , Qualidade de VidaRESUMO
BACKGROUND: Guillain-Barré syndrome (GBS) is an acute inflammatory neuropathy with a heterogeneous presentation. Although some evidences support the role of autoantibodies in its pathogenesis, the target antigens remain unknown in a substantial proportion of GBS patients. The objective of this study is to screen for autoantibodies targeting peripheral nerve components in Guillain-Barré syndrome. METHODS: Autoantibody screening was performed in serum samples from all GBS patients included in the International GBS Outcome study by 11 different Spanish centres. The screening included testing for anti-ganglioside antibodies, anti-nodo/paranodal antibodies, immunocytochemistry on neuroblastoma-derived human motor neurons and murine dorsal root ganglia (DRG) neurons, and immunohistochemistry on monkey peripheral nerve sections. We analysed the staining patterns of patients and controls. The prognostic value of anti-ganglioside antibodies was also analysed. RESULTS: None of the GBS patients (n = 100) reacted against the nodo/paranodal proteins tested, and 61 (61%) were positive for, at least, one anti-ganglioside antibody. GBS sera reacted strongly against DRG neurons more frequently than controls both with IgG (6% vs 0%; p = 0.03) and IgM (11% vs 2.2%; p = 0.02) immunodetection. No differences were observed in the proportion of patients reacting against neuroblastoma-derived human motor neurons. Reactivity against monkey nerve tissue was frequently detected both in patients and controls, but specific patterns were only detected in GBS patients: IgG from 13 (13%) patients reacted strongly against Schwann cells. Finally, we confirmed that IgG anti-GM1 antibodies are associated with poorer outcomes independently of other known prognostic factors. CONCLUSION: Our study confirms that (1) GBS patients display a heterogeneous repertoire of autoantibodies targeting nerve cells and structures; (2) gangliosides are the most frequent antigens in GBS patients and have a prognostic value; (3) further antigen-discovery experiments may elucidate other potential antigens in GBS.