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Gastrointestinal tuberculosis is an uncommon entity, in which clinical presentation can be widely variable, from mild and nonspecific symptoms to an acute abdomen and gastrointestinal bleeding. Gastric involvement by Mycobacterium tuberculosis is rare, especially when it occurs without other recognized infectious foci - primary gastric tuberculosis - with only a few reported cases. Endoscopic findings can be very heterogeneous, from areas of hyperemia to pseudotumor lesions. We present a case of primary gastric tuberculosis in an immunocompetent patient, in which the absence of an epidemiological context and nonspecific endoscopic findings led to a delay in the diagnosis. Bite-on-bite biopsies proved to be essential, allowing to obtain samples from deeper layers of the submucosa where M. tuberculosis was identified. This case aimed to increase awareness for this entity, especially in endemic countries or regions with a high prevalence of tuberculosis since the diagnosis is based mainly on a high index of suspicion.
A tuberculose gastrointestinal é uma entidade pouco comum, com uma apresentação clínica amplamente variável, desde sintomas ligeiros e inespecíficos até quadros de abdómen agudo e hemorragia digestiva. O envolvimento gástrico pelo Mycobacterium tuberculosis é raro, especialmente quando ocorre sem outros focos infeciosos reconhecidos tuberculose gástrica primária , havendo apenas alguns casos descritos na literatura. Os achados endoscópicos podem ser muito heterogéneos, variando desde áreas de mucosa hiperemiada até lesões pseudo-tumorais. Apresentamos o caso de uma doente imunocompetente com diagnóstico de tuberculose gástrica primária, em que a ausência de um contexto epidemiológico e achados endoscópicos inespecíficos conduziram a um atraso no diagnóstico. As biópsias sobre biópsias mostraram ser essenciais para o diagnóstico, pois permitiram obter amostras de camadas mais profundas da submucosa do antro gástrico onde foi identificado o agente infecioso. Este caso pretende sensibilizar para existência desta entidade, especialmente em países endémicos ou regiões com alta prevalência de tuberculose, uma vez que o seu diagnóstico implica um elevado grau de suspeição.
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N6-methyladenosine (m6A) is a mRNA modification with important roles in gene expression. In African trypanosomes, this post-transcriptional modification is detected in hundreds of transcripts and it affects the stability of the variant surface glycoprotein (VSG) transcript in the proliferating blood stream form. However, how the m6A landscape varies across the life cycle remains poorly defined. Using full-length, non-fragmented RNA, we immunoprecipitated and sequenced m6A-modified transcripts across three life cycle stages of Trypanosoma brucei - slender (proliferative), stumpy (quiescent), and procyclic forms (proliferative). We found that 1037 transcripts are methylated in at least one of these three life cycle stages. While 21% of methylated transcripts are common in the three stages of the life cycle, globally each stage has a distinct methylome. Interestingly, 47% of methylated transcripts are detected in the quiescent stumpy form only, suggesting a critical role for m6A when parasites exit the cell cycle and prepare for transmission by the Tsetse fly. In this stage, we found that a significant proportion of methylated transcripts encodes for proteins involved in RNA metabolism, which is consistent with their reduced transcription and translation. Moreover, we found that not all major surface proteins are regulated by m6A, as procyclins are not methylated, and that, within the VSG repertoire, not all VSG transcripts are demethylated upon parasite differentiation to procyclic form. This study reveals that the m6A regulatory landscape is specific to each life cycle stage, becoming more pervasive as T. brucei exits the cell cycle.
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Arterial bleeding is a dreadful late complication of acute pancreatitis that usually mandates emergent endovascular embolization or surgery. We present the case of a massive arterial bleeding resulting from fistulization of a pseudocyst to the stomach, which was successfully managed by endoscopic injection of cyanoacrylate.
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Trypanosoma brucei causes African trypanosomiasis, colonizing adipose tissue and inducing weight loss. Here we investigated the molecular mechanisms responsible for adipose mass loss and its impact on disease pathology. We found that lipolysis is activated early in infection. Mice lacking B and T lymphocytes fail to upregulate adipocyte lipolysis, resulting in higher fat mass retention. Genetic ablation of the rate-limiting adipose triglyceride lipase specifically from adipocytes (AdipoqCre/+-Atglfl/fl) prevented the stimulation of adipocyte lipolysis during infection, reducing fat mass loss. Surprisingly, these mice succumbed earlier and presented a higher parasite burden in the gonadal adipose tissue, indicating that host lipolysis limits parasite growth. Consistently, free fatty acids comparable with those of adipose interstitial fluid induced loss of parasite viability. Adipocyte lipolysis emerges as a mechanism controlling local parasite burden and affecting the loss of fat mass in African trypanosomiasis.
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Trypanosoma brucei brucei , Tripanosomiasis Africana , Animales , Ratones , Lipólisis/genética , Trypanosoma brucei brucei/metabolismo , Lipasa/genética , Adipocitos/metabolismo , Adipocitos/patología , ObesidadRESUMEN
BACKGROUND: Immunosuppressive therapy used in the treatment of inflammatory bowel disease (IBD) is known to reduce vaccine immunogenicity. AIMS: This study aimed to 1) predict the humoral response elicited by SARS-CoV-2 vaccination in IBD patients based on their ongoing treatment and other relevant patient and vaccine characteristics and 2) assess the humoral response to a booster dose of mRNA vaccine. METHODS: We conducted a prospective study in adult IBD patients. Anti-spike (S) IgG antibodies were measured after initial vaccination and again after one booster dose. A multiple linear regression model was created to predict anti-S antibody titer following initial complete vaccination in different therapeutic groups (no immunosuppression, anti-TNF, immunomodulators and combination therapy). A two-tailed Wilcoxon test for two dependent groups was performed to compare anti-S values before and after the booster dose. RESULTS: Our study included 198 IBD patients. The multiple linear regression identified anti-TNF and combination therapy (versus no immunosuppression), current smoking, viral vector (versus mRNA) vaccine and interval between vaccination and anti-S measurement as statistically significant predictors of the log anti-S antibody levels (p < 0.001). No statistically significant differences were found between no immunosuppression and immunomodulators (p = 0.349) and between anti-TNF and combination therapy (p = 0.997). Statistically significant differences for anti-S antibody titer before and after the booster dose of mRNA SARS-CoV-2 vaccine were found, both for non-anti-TNF and anti-TNF groups. CONCLUSIONS: Anti-TNF treatment (either alone or in combination therapy) is associated with lower anti-S antibody levels. Booster mRNA doses seem to increase anti-S both in non-anti-TNF and anti-TNF treated patients. Special attention should be paid to this group of patients when planning vaccination schemes.
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Vacunas contra la COVID-19 , COVID-19 , Enfermedades Inflamatorias del Intestino , Adulto , Humanos , Adyuvantes Inmunológicos , Anticuerpos Antivirales , COVID-19/prevención & control , Vacunas contra la COVID-19/inmunología , Inmunoglobulina G , Enfermedades Inflamatorias del Intestino/tratamiento farmacológico , Necrosis , Estudios Prospectivos , SARS-CoV-2 , Vacunación , Inhibidores del Factor de Necrosis Tumoral/efectos adversosRESUMEN
When Trypanosoma brucei parasites, the causative agent of sleeping sickness, colonize the adipose tissue, they rewire gene expression. Whether this adaptation affects population behavior and disease treatment remained unknown. By using a mathematical model, we estimate that the population of adipose tissue forms (ATFs) proliferates slower than blood parasites. Analysis of the ATFs proteome, measurement of protein synthesis and proliferation rates confirm that the ATFs divide on average every 12 h, instead of 6 h in the blood. Importantly, the population of ATFs is heterogeneous with parasites doubling times ranging between 5 h and 35 h. Slow-proliferating parasites remain capable of reverting to the fast proliferation profile in blood conditions. Intravital imaging shows that ATFs are refractory to drug treatment. We propose that in adipose tissue, a subpopulation of T. brucei parasites acquire a slow growing behavior, which contributes to disease chronicity and treatment failure.
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Tejido AdiposoRESUMEN
Lesch-Nyhan syndrome (LNS) is an inherited recessive X-related disorder caused by a deficiency of the purine salvage enzyme hypoxanthine-guanine phosphoribosyltransferase. It is characterized by dystonia and compulsive self-mutilation, in particular, biting behavior on the oral mucosa, tongue, lips, fingers, and shoulders, typically before one year of age. The majority of these patients require several procedures, including dental extractions, to prevent significant secondary lesions. This article aims to report a clinical case of a 12-year-old boy with an LNS diagnosis who was referred to the Paediatric Stomatology Department of Central Lisbon University Hospital. Since the age of eight, the patient had displayed self-harm behavior, with arm and oral injuries. On evaluation, he presented with deep ulcerated lesions on the lips and tongue, with substance loss associated with a significant decrease in food intake and consequent weight loss. The management included conservative therapy with gabapentin, lorazepam, and botulinum toxin injections. A successful reduction of self-mutilation with no signs of new lesions in the oral cavity and an improvement in nutritional status were reported. The therapeutic approach is essential to provide the best quality of life for patients and their caregivers. To delay radical treatments, multiple therapeutic options can be used. The oral pathology team considered that the most appropriate therapy was botulinum toxin A injections along with therapeutic adjustment, which was effective in wound healing and self-mutilation behavior ceasing at the two-month follow-up.
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Sclerotic fibroma, also known as storiform collagenoma, is a rare benign tumor that grows on the skin, but it can also appear, less frequently, in the oral mucosa. It can present as part of Cowden syndrome manifestation, especially when multiple lesions are encountered, but it may also appear as a solitary, sporadic lesion in healthy individuals. We describe a patient, diagnosed with Cowden syndrome, who presented with a sclerotic fibroma in the oral mucosa, which is a very uncommon manifestation of Cowden syndrome.
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Trypanosoma congolense causes a syndrome of variable severity in animals in Africa. Cerebral trypanosomiasis is a severe form, but the mechanism underlying this severity remains unknown. We developed a mouse model of acute cerebral trypanosomiasis and characterized the cellular, behavioral, and physiological consequences of this infection. We show large parasite sequestration in the brain vasculature for long periods of time (up to 8 hr) and extensive neuropathology that associate with ICAM1-mediated recruitment and accumulation of T cells in the brain parenchyma. Antibody-mediated ICAM1 blocking and lymphocyte absence reduce parasite sequestration in the brain and prevent the onset of cerebral trypanosomiasis. Here, we establish a mouse model of acute cerebral trypanosomiasis and we propose a mechanism whereby parasite sequestration, host ICAM1, and CD4+ T cells play a pivotal role.
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Parásitos , Trypanosoma congolense , Tripanosomiasis Africana , Tripanosomiasis , Animales , Modelos Animales de Enfermedad , Ratones , Tripanosomiasis Africana/parasitologíaRESUMEN
Intravital microscopy (IVM) involves surgical procedures to expose the internal organs of live anesthetized animals to visualize fluorescently labeled components in situ, in vivo at subcellular resolution. Here, we provide an IVM protocol for time-lapse imaging of dynamic Trypanosoma brucei-host interactions in ten mammalian organs and in systemic circulation. We describe intraperitoneal or intradermal injection of mice with T.brucei. We then detail surgical procedures to prepare ten organs for IVM, followed by imaging of host-T. brucei interactions. For complete details on the use and execution of this protocol, please refer to De Niz et al. (2021).
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Trypanosoma brucei brucei , Animales , Microscopía Intravital/métodos , Ratones , RoedoresRESUMEN
The parasite Trypanosoma brucei causes African sleeping sickness that is fatal to patients if untreated. Parasite differentiation from a replicative slender form into a quiescent stumpy form promotes host survival and parasite transmission. Long noncoding RNAs (lncRNAs) are known to regulate cell differentiation in other eukaryotes. To determine whether lncRNAs are also involved in parasite differentiation, we used RNA sequencing to survey the T. brucei genome, identifying 1428 previously uncharacterized lncRNA genes. We find that grumpy lncRNA is a key regulator that promotes parasite differentiation into the quiescent stumpy form. This function is promoted by a small nucleolar RNA encoded within the grumpy lncRNA. snoGRUMPY binds to messenger RNAs of at least two stumpy regulatory genes, promoting their expression. grumpy overexpression reduces parasitemia in infected mice. Our analyses suggest that T. brucei lncRNAs modulate parasite-host interactions and provide a mechanism by which grumpy regulates cell differentiation in trypanosomes.
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Campylobacter rectus is considered to be a primary periodontal pathogen that is rarely identified in extraoral specimens. We report a case of pleural empyema caused by Campylobacter rectus: the pathogen was isolated in the drained pleural fluid sample. Since the patient had previously undergone multiple antibiotic treatments, oral cultures were highly unlikely to be positive, although poor dental hygiene appears to be the leading risk factor for C. rectus systemic infections. The present case illustrates that C. rectus can be a cause of not only periodontal disease but also pulmonary infection.
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RNA modifications are important regulators of gene expression1. In Trypanosoma brucei, transcription is polycistronic and thus most regulation happens post-transcriptionally2. N6-methyladenosine (m6A) has been detected in this parasite, but its function remains unknown3. Here we found that m6A is enriched in 342 transcripts using RNA immunoprecipitation, with an enrichment in transcripts encoding variant surface glycoproteins (VSGs). Approximately 50% of the m6A is located in the poly(A) tail of the actively expressed VSG transcripts. m6A residues are removed from the VSG poly(A) tail before deadenylation and mRNA degradation. Computational analysis revealed an association between m6A in the poly(A) tail and a 16-mer motif in the 3' untranslated region of VSG genes. Using genetic tools, we show that the 16-mer motif acts as a cis-acting motif that is required for inclusion of m6A in the poly(A) tail. Removal of this motif from the 3' untranslated region of VSG genes results in poly(A) tails lacking m6A, rapid deadenylation and mRNA degradation. To our knowledge, this is the first identification of an RNA modification in the poly(A) tail of any eukaryote, uncovering a post-transcriptional mechanism of gene regulation.
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Procesamiento Postranscripcional del ARN , Trypanosoma brucei brucei , Glicoproteínas Variantes de Superficie de Trypanosoma , Regiones no Traducidas 3'/genética , Adenosina/análogos & derivados , Regulación de la Expresión Génica , ARN/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismo , Transcripción Genética , Trypanosoma brucei brucei/genética , Glicoproteínas Variantes de Superficie de Trypanosoma/genéticaRESUMEN
This study aimed to determine the impact of systematic coronary computed tomographic angiography (CCTA) use following an abnormal non-invasive ischemia test (NIST) on patient selection strategy for invasive coronary angiography (ICA). In patients with suspected stable coronary artery disease (CAD), NIST use frequently results in sub-optimal diagnostic and revascularization yields of ICA. This randomized clinical trial, conducted at a single academic tertiary center, selected 220 symptomatic patients with mild-to-moderately abnormal NIST results who were referred for ICA. Patients received either the originally intended ICA (n = 105) or CCTA (n = 115). The primary endpoint was the diagnostic yield of ICA in each group. Revascularization yield and major adverse cardiovascular events at 12 months were also assessed. The patients were 69 ± 9 years old, 60% were men, and 31% had typical angina. Mean pre-test probability of obstructive CAD was 34%. Overall prevalence of obstructive CAD was 37.7% on the index angiographic procedure. In the CCTA group, ICA was cancelled by referring physicians in 83 patients (72.2%) after receiving CCTA results. For those undergoing ICA, diagnostic (84.4% vs. 41.7%, p<0.001) and revascularization (71.9% vs. 38.8%, p = 0.001) yields were significantly higher for CCTA-guided ICA than for standard NIST-guided ICA. Mean cumulative radiation exposure was significantly lower in the CCTA-guided ICA arm than in the NIST-guided ICA arm (12 ± 9 vs. 16 ± 10 mSv, respectively, p = 0.024). There were no significant differences in the primary safety endpoint rates between the strategies (p = 0.439). In patients with suspected CAD and mild-to-moderately abnormal ischemia tests, a diagnostic strategy including CCTA as a gatekeeper is safe and effective and significantly improves diagnostic and revascularization yields of ICA.
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Elastic banding and sclerotherapy are the two most commonly performed instrumental therapies in the treatment of symptomatic internal hemorrhoids. Promising results have been shown with sclerotherapy using 2 % polidocanol foam. The present study aimed to evaluate the efficacy and safety of polidocanol foam in the treatment of symptomatic internal hemorrhoids.
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Hemorroides , Escleroterapia , Hemorroides/terapia , Humanos , Polidocanol/uso terapéutico , Polietilenglicoles/uso terapéutico , Soluciones Esclerosantes/uso terapéutico , Resultado del TratamientoRESUMEN
BACKGROUND: Multidrug-resistant organisms (MDROs) are a reality that can alter the paradigm of treatment and prevention of infection in patients with liver cirrhosis (LC). OBJECTIVE: Identify risk factors for the occurrence of MDROs in patients with LC. PATIENTS AND METHODS: Prospective study from October 2017 to March 2018 in consecutively hospitalized patients with decompensated LC with infection. Blood, urine and ascitic fluid cultures were analyzed. A p-value ≤0.05 was considered statistically significant. RESULTS: MDROs isolated in 18 of 52 episodes of infection. MDROs were associated with the use of proton pump inhibitors (PPIs) (p=0.0312), antibiotic therapy in the last 90 days (p=0.0033) and discharge within preceding 30 days or current hospitalization above 48h (p=0.0082). There was higher 90-day mortality in patients with MDROs infection (71.4% versus 35.7%, p=0.0316). CONCLUSION: MDROs infections were prevalent in this cohort and associated with 90-day mortality. Use of PPIs and antibiotics increased the risk of MDROs infections, suggesting that its prescription should be restricted to formal indication. Hospitalization was associated with the onset of MDROs, so LC patients should stay at the hospital the least possible. It is relevant to investigate other factors predisposing to the emergence of these microorganisms, in order to prevent it.
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Infecciones Bacterianas/microbiología , Infección Hospitalaria/microbiología , Farmacorresistencia Bacteriana Múltiple , Cirrosis Hepática/microbiología , Antibacterianos/uso terapéutico , Líquido Ascítico/microbiología , Infecciones Bacterianas/tratamiento farmacológico , Infecciones Bacterianas/epidemiología , Infecciones Bacterianas/mortalidad , Infección Hospitalaria/tratamiento farmacológico , Infección Hospitalaria/epidemiología , Infección Hospitalaria/mortalidad , Femenino , Humanos , Tiempo de Internación , Cirrosis Hepática/mortalidad , Masculino , Persona de Mediana Edad , Alta del Paciente , Estudios Prospectivos , Inhibidores de la Bomba de Protones/uso terapéutico , Factores de Riesgo , Factores de TiempoRESUMEN
BACKGROUND: European Society of Gastrointestinal Endoscopy (ESGE) recommends needle-knife fistulotomy (NKF) as the preferred precut technique in cases when standard cannulation techniques fail. Despite scarce scientific evidence, flat and diverticular papillae are thought not to be ideal for NKF, as they are associated with poor outcomes. The present study aimed to determine the outcomes of the use of NKF in relation to flat and intradiverticular papillae. METHODS: This prospective multicenter study enrolled consecutive patients, evidencing naïve flat (group A, n = 49) or diverticular papilla (group B, n = 28), who underwent NKF after failure of standard cannulation techniques. Diverticular morphology was subdivided into intradiverticular (group B1, n = 14) and diverticular border papillae (group B2, n = 14), using a previously validated endoscopic classification of the major papilla. The success of biliary cannulation at initial endoscopic retrograde cholangiopancreatography (ERCP), overall biliary cannulation, overall cannulation time, and the rate of adverse events were assessed in the study. RESULTS: The initial cannulation rates were 93.9%, 64.3% and 71.4% for group A, B1, and B2, respectively (P = 0.005); overall cannulation rates after a second ERCP were 98.0%, 92.9% and 85.7%, respectively (P = 0.134). Adverse events occurred in 11.7% of patients, with post-ERCP pancreatitis (PEP) being the most common adverse event (10.4%). Although there was a trend towards a higher incidence of PEP in flat papillae, univariate and multivariate analyses did not show any significant relationship between pancreatitis and trainee involvement, papillary morphology, nor overall cannulation time. CONCLUSIONS: Although flat papillae are associated with high success rates of biliary cannulation using NKF, the rate of PEP is not negligible. NKF is feasible in diverticular papillae, but it is associated with a modest success rate in the initial ERCP.
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Pancreatitis , Esfinterotomía Endoscópica , Cateterismo/efectos adversos , Cateterismo/métodos , Colangiopancreatografia Retrógrada Endoscópica/efectos adversos , Colangiopancreatografia Retrógrada Endoscópica/métodos , Humanos , Pancreatitis/etiología , Estudios Prospectivos , Estudios Retrospectivos , Esfinterotomía Endoscópica/efectos adversosRESUMEN
BACKGROUND: Peroral cholangioscopy (POC)-guided lithotripsy is an effective treatment for difficult biliary stones. A clear definition of factors associated with the efficacy of POC-guided lithotripsy in one session and the performance of electrohydraulic lithotripsy (EHL) and laser lithotripsy (LL) have not clearly emerged. METHODS: This was a non-randomized prospective multicenter study of all consecutive patients who underwent POC lithotripsy (using EHL and/or LL) for difficult biliary stones. The primary endpoint of the study was the number of sessions needed to achieve complete ductal clearance and the factors associated with this outcome. Secondary endpoints included the evaluated efficacies of LL and EHL. RESULTS: Ninety-four patients underwent 113 procedures of EHL or LL. Complete ductal clearance was obtained in 93/94 patients (98.94%). In total, 80/94 patients (85.11%) achieved stone clearance in a single session. In the multivariate analysis, stone size was independently associated with the need for multiple sessions to achieve complete ductal clearance (odds ratio = 1.146, 95% confidence interval: 1.055-1.244; p = 0.001). Using ROC curves and the Youden index, 22 mm was found to be the optimal cutoff for stone size (95% confidence interval: 15.71-28.28; p < 0.001). The majority of the patients (62.8%) underwent LL in the first session. Six patients failed the first session with EHL after using two probes and therefore were crossed over to LL, obtaining ductal clearance in a single additional session with a single LL fiber. EHL was significantly associated with a larger number of probes (2.0 vs. 1.02) to achieve ductal clearance (p < 0.01). The mean procedural time was significantly longer for EHL than for LL [72.1 (SD 16.3 min) versus 51.1 (SD 10.5 min)] (p < 0.01). CONCLUSIONS: POC is highly effective for difficult biliary stones. Most patients achieved complete ductal clearance in one session, which was significantly more likely for stones < 22 mm. EHL was significantly associated with the need for more probes and a longer procedural time to achieve ductal clearance.
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Procedimientos Quirúrgicos del Sistema Biliar , Cálculos , Cálculos Biliares , Litotripsia por Láser , Litotricia , Colangiopancreatografia Retrógrada Endoscópica/métodos , Cálculos Biliares/cirugía , Humanos , Litotricia/métodos , Litotripsia por Láser/métodos , Estudios Prospectivos , Resultado del TratamientoRESUMEN
An intriguing and remarkable feature of African trypanosomes is their antigenic variation system, mediated by the variant surface glycoprotein (VSG) family and fundamental to both immune evasion and disease epidemiology within host populations. Recent studies have revealed that the VSG repertoire has a complex evolutionary history. Sequence diversity, genomic organization, and expression patterns are species-specific, which may explain other variations in parasite virulence and disease pathology. Evidence also shows that we may be underestimating the extent to what VSGs are repurposed beyond their roles as variant antigens, establishing a need to examine VSG functionality more deeply. Here, we review sequence variation within the VSG gene family, and highlight the many opportunities to explore their likely diverse contributions to parasite survival.