Endoscopic Submucosal Dissection for Resections Larger than 10 cm: Outcomes from a Portuguese Center.

Background: Endoscopic submucosal dissection (ESD) is a minimally invasive technique for en bloc resection of superficial neoplastic lesions, independent of their size. However, for giant gastrointestinal superficial neoplasia, the risk of invasive cancer is higher, and ESD is typically challenging. Despite the increasing literature on giant resections, data on their efficacy and safety are still lacking. Objective: The aim of this study was to describe ESD outcomes from a Portuguese center, compare them with other international studies, and analyze the possible risk factors influencing outcomes. Methods: We conducted a retrospective single-center review using a prospectively collected database, including patients with rectal ESD resections larger than 10 cm, between January 2016 and December 2021. Clinical, procedural, and pathological data were collected and analyzed. Revision of the literature for comparison with international results was done through PubMed. Data were analyzed and statistical analysis performed, using Microsoft Excel and SPSS, to identify significant risk factors. Results: The study included 15 rectal resections, with a mean diameter of 140.9 mm (range 105-270), corresponding to lesions of 125.9 mm (87-238). The overall en bloc resection rate was 100% (n = 15). According to ESGE criteria, procedure was considered curative in 53.3% (n = 8), non-curative with high risk in 13.3% (n = 2), and local-risk recurrence in 33.3% (n = 5). Adverse events occurred in 26.7% (n = 4): 1 minor perforation and 3 stenosis, most endoscopically managed. For non-curative resections with local-risk recurrence, surveillance without adjuvant therapy was performed in all cases. For high-risk non-curative resections, surgery was performed in 1 patient and adjuvant chemoradiation therapy in another. Follow-up (mean 16 months) demonstrated a recurrence rate of 0%. Statistical analysis revealed resection size ≥20 cm as a risk factor for perforation (p value 0.067), and involvement of ≥90% of the circumference and procedural time ≥4 h as risk factors for stenosis (p value 0.029 and 0.009, respectively). Conclusions: Although challenging, ESD for giant lesions seems effective and safe, with a still relevant rate of complications, which were mostly endoscopically treated. Rigorous characterization of lesions is crucial to predict and avoid complications or the need for therapy escalation.

Background: A dissecao endoscopica da submucosa (DES) e uma tecnica minimamente invasiva para ressecao em bloco de tumores superficiais, independentemente do seu tamanho. No entanto, nas neoplasias superficiais gastrointestinais gigantes, o risco de cancro invasivo esta aumentado e a DES e tipicamente desafiante. Apesar do incremento da literatura acerca de ressecoes gigantes, dados da sua eficacia e seguranca sao ainda escassos. Objetivo: Descricao de outcomes de DES de um centro portugues e comparacao com estudos internacionais. Analise de eventuais fatores de risco influenciando os outcomes. Métodos: Revisao retrospetiva de um centro, usando a sua base de dados prospectivamente colhida, incluindo pacientes com ressecoes rectais por DES maiores que 10 cm, entre janeiro 2016 e dezembro 2021. Dados clinicos, endoscopicos e patologicos foram colhidos e analisados. A literatura foi revista atraves do PubMed, para comparacao com resultados internacionais. A analise dos resultados e estatistica foi realizada, utilizando o Microsoft Excel e SPSS, para a identificacao de fatores de risco com impacto significativo nos outcomes. Resultados: O estudo incluiu um total de 15 ressecoes retais, com uma media de diametros de 140,9 mm (intervalo 105­270), correspondendo a lesoes 125,9 mm (intervalo 87­238). A taxa de ressecao em bloco foi de 100% (n = 15). Segundo os criterios da ESGE, o procedimento foi curativo em 53,3% (n = 8), nao curativo com alto risco em 13,3% (n = 2) e com risco de recorrencia local em 33,3% (n = 5). Eventos adversos ocorreram em 26,7% (n = 4): 1 microperfuracao e 3 estenoses, a maioria geridas endoscopicamente. Os 5 casos nao curativos com risco de recorrencia local ficaram apenas sob vigilancia. Nas resseccoes nao curativas de alto risco, um paciente foi submetido a cirurgia e outro a quimioradioterapia adjuvante. O follow-up (media de 16 meses) demonstrou uma taxa de recorrencia de 0%. A analise estatistica demonstrou o tamanho da resseccao ≥20 cm como fator de risco significativo para perfuracao (p value 0.067); e envolvimento de ≥ 90% da circunferencia do lumen e tempo de procedimento ≥4h como fatores de risco significativos para estenose (p value 0.029 e 0.009, respetivamente). Conclusão: Apesar de desafiante, a DES para lesoes gigantes parece eficaz e segura, com uma taxa de complicacoes importante, possiveis de tratamento endoscopico. A caracterizacao rigorosa destas lesoes e crucial para predizer e evitar complicacoes ou a necessidade de escalada terapeutica.

Optimization of Phenolic Compounds Extraction and Antioxidant Activity from Inonotus hispidus Using Ultrasound-Assisted Extraction Technology.

The use of ultrasound-assisted extraction (UAE) of bioactive compounds has been increasing because it is a good alternative to the conventional extraction methods. UAE was used to maximize total polyphenol content (TPC), 2,2-diphenyl-1-picrylhydrazyl (DPPH) scavenging capacity, and ferric reducing antioxidant power (FRAP) of the mushroom Inonotus hispidus using response surface methodology (RSM). Firstly, the effect of 40% (v/v) ethanol and 80% (v/v) methanol on the TPC, DPPH scavenging capacity, and FRAP was evaluated. The ethanolic extracts showed a significantly higher (p < 0.0001) TPC, DPPH scavenging capacity, and FRAP than the methanolic extracts. The best condition to produce an extract with the higher TPC and antioxidant activity was achieved when using 40% (v/v) ethanol, a ratio of 75 mL/g, and an extraction time of 20 min. The chromatographic profile of the extract obtained in the optimized condition revealed that hispidin is the main polyphenol present in the extracts of I. hispidus, representing, together with hispidin-like compounds, the majority of the phenolic compounds (159.56 µg/g DW out of 219.01 µg/g DW). The model allowed us to optimize the conditions to maximize the extraction of phenolic compounds with antioxidant activity from I. hispidus, demonstrating its potential as a source of antioxidant compounds, with possible industrial, pharmaceutical, and food applications.

A “window” in the duodenal bulb: an atypical presentation of chronic cholecystitis

A 74-year-old male presented with melena and fatigue, without fever or abdominal pain. Laboratory examination revealed anemia, leukocytosis, elevated C-reactive protein levels and conjugated hyperbilirubinemia with elevated liver enzymes. Upper endoscopy identified blood in the stomach and duodenum and a 6 mm hole in the anterosuperior surface of the duodenal bulb with spontaneous drainage of a bloody brownish content. The mucosa surrounding the hole was normal and there was a discrete mucosal flap that throbbed with air insufflation. Abdominal computed tomography identified a fistulous tract between the duodenal bulb and the gallbladder with a 2 mm caliber, suggesting a cholecystoduodenal fistula. Diagnosis is often difficult because symptoms are nonspecific and variable but gastrointestinal bleeding is a rare clinical presentation. (AU)

A "window" in the duodenal bulb: an atypical presentation of chronic cholecystitis.

A 74-year-old male presented with melena and fatigue, without fever or abdominal pain. Laboratory examination revealed anemia, leukocytosis, elevated C-reactive protein levels and conjugated hyperbilirubinemia with elevated liver enzymes. Upper endoscopy identified blood in the stomach and duodenum and a 6 mm hole in the anterosuperior surface of the duodenal bulb with spontaneous drainage of a bloody brownish content. The mucosa surrounding the hole was normal and there was a discrete mucosal flap that throbbed with air insufflation. Abdominal computed tomography identified a fistulous tract between the duodenal bulb and the gallbladder with a 2 mm caliber, suggesting a cholecystoduodenal fistula. Diagnosis is often difficult because symptoms are nonspecific and variable but gastrointestinal bleeding is a rare clinical presentation.

Left-right side-specific endocrine signaling complements neural pathways to mediate acute asymmetric effects of brain injury.

Brain injuries can interrupt descending neural pathways that convey motor commands from the cortex to spinal motoneurons. Here, we demonstrate that a unilateral injury of the hindlimb sensorimotor cortex of rats with completely transected thoracic spinal cord produces hindlimb postural asymmetry with contralateral flexion and asymmetric hindlimb withdrawal reflexes within 3 hr, as well as asymmetry in gene expression patterns in the lumbar spinal cord. The injury-induced postural effects were abolished by hypophysectomy and were mimicked by transfusion of serum from animals with brain injury. Administration of the pituitary neurohormones ß-endorphin or Arg-vasopressin-induced side-specific hindlimb responses in naive animals, while antagonists of the opioid and vasopressin receptors blocked hindlimb postural asymmetry in rats with brain injury. Thus, in addition to the well-established involvement of motor pathways descending from the brain to spinal circuits, the side-specific humoral signaling may also add to postural and reflex asymmetries seen after brain injury.

Brain trauma or a stroke often lead to severe problems in posture and movement. These injuries frequently occur only on one side, causing asymmetrical motor changes: damage to the left brain hemisphere triggers abnormal contractions of the right limbs, and vice-versa. The injuries can disrupt neural tracts between the brain and the spinal cord, the structure that conveys electric messages to muscles. However, research has also shed light on new actors: the hormones released into the bloodstream by the pituitary gland. Similar to the effects of brain lesions, several of these molecules cause asymmetric posture in healthy rats. In fact, a group of hormones can trigger muscle contraction of the left back leg, and another of the right one. Could pituitary hormones mediate the asymmetric effects of brain injuries? To investigate this question, Lukoyanov, Watanabe, Carvalho, Kononenko, Sarkisyan et al. focused on rats in which the connection between the brain and the spinal cord segments that control the hindlimbs had been surgically removed. This stopped transmission of electric messages from the brain to muscles in the back legs. Strikingly, lesions on one side of the brain in these animals still led to asymmetric posture, with contraction of the leg on the opposite side of the body. These effects were abolished when the pituitary gland was excised. Postural asymmetry also emerged when blood serum from injured rats was injected into healthy animals. The findings suggest that hormones play an essential role in signalling from the brain to the spinal cord. Further experiments identified that two pituitary hormones, ß-endorphin and Arg-vasopressin, induced contraction of the right but not the left hindlimb of healthy animals. In addition, small molecules that inhibit these hormones could block the deficits seen on the right side after an injury on the left hemisphere of the brain. Taken together, these results show that neurons in the spinal cord are not just controlled by the neural tracts that descend from the brain, but also by hormones which have left-right side-specific actions. This unique signalling could be a part of a previously unknown hormonal mechanism that selectively targets either the left or the right side of the body. This knowledge could help to design side-specific treatments for stroke and brain trauma.

Coordinated expression of the renin-angiotensin genes in the lumbar spinal cord: Lateralization and effects of unilateral brain injury.

In spite of its apparent symmetry, the spinal cord is asymmetric in its reflexes and gene expression patterns including leftward expression bias of the opioid and glutamate genes. To examine whether this is a general phenomenon for neurotransmitter and neurohormonal genes, we here characterized expression and co-expression (transcriptionally coordinated) patterns of genes of the renin-angiotensin system (RAS) that is involved in neuroprotection and pathological neuroplasticity in the left and right lumbar spinal cord. We also tested whether the RAS expression patterns were affected by unilateral brain injury (UBI) that rewired lumbar spinal neurocircuits. The left and right halves of the lumbar spinal cord were analysed in intact rats, and rats with left- or right-sided unilateral cortical injury, and left- or right-sided sham surgery. The findings were (i) lateralized expression of the RAS genes Ace, Agtr2 and Ren with higher levels on the left side; (ii) the asymmetry in coordination of the RAS gene expression that was stronger on the right side; (iii) the decay in coordination of co-expression of the RAS and neuroplasticity-related genes induced by the right-side but not left-side sham surgery and UBI; and (iv) the UBI-induced shift to negative regulatory interactions between RAS and neuroplasticity-related genes on the contralesional spinal side. Thus, the RAS genes may be a part of lateralized gene co-expression networks and have a role in a side-specific regulation of spinal neurocircuits.

Left-Right Side-Specific Neuropeptide Mechanism Mediates Contralateral Responses to a Unilateral Brain Injury.

Neuropeptides are implicated in control of lateralized processes in the brain. A unilateral brain injury (UBI) causes the contralesional sensorimotor deficits. To examine whether opioid neuropeptides mediate UBI induced asymmetric processes we compared effects of opioid antagonists on the contralesional and ipsilesional hindlimb responses to the left-sided and right-sided injury in rats. UBI induced hindlimb postural asymmetry (HL-PA) with the contralesional hindlimb flexion, and activated contralesional withdrawal reflex of extensor digitorum longus (EDL) evoked by electrical stimulation and recorded with EMG technique. No effects on the interossei (Int) and peroneaus longus (PL) were evident. The general opioid antagonist naloxone blocked postural effects, did not change EDL asymmetry while uncovered cryptic asymmetry in the PL and Int reflexes induced by UBI. Thus, the spinal opioid system may either mediate or counteract the injury effects. Strikingly, effects of selective opioid antagonists were the injury side-specific. The µ-antagonist ß-funaltrexamine (FNA) and κ-antagonist nor-binaltorphimine (BNI) reduced postural asymmetry after the right but not left UBI. In contrast, the δ-antagonist naltrindole (NTI) inhibited HL-PA after the left but not right-side brain injury. The opioid gene expression and opioid peptides were lateralized in the lumbar spinal cord, and coordination between expression of the opioid and neuroplasticity-related genes was impaired by UBI that together may underlie the side-specific effects of the antagonists. We suggest that mirror-symmetric neural circuits that mediate effects of left and right brain injury on the contralesional hindlimbs are differentially controlled by the lateralized opioid system.

Mineralocorticoid Receptor Antagonists Eplerenone and Spironolactone Modify Adrenal Cortex Morphology and Physiology.

Mineralocorticoid receptor antagonists (MRAs) are a class of anti-hypertensive drugs that act by blocking aldosterone action. The aim of this study was to evaluate whether the MRAs spironolactone and eplerenone influence adrenal cortical physiology and morphology. Spontaneous hypertensive rats (SHR, n = 18) and normotensive rats (WKY, n = 18) were randomly exposed to a daily dose of spironolactone (n = 6), eplerenone (n = 6), or no drug (n = 6) over 28 days. After that, aldosterone, corticosterone, and 11-deoxycorticosterone plasma concentrations were quantified. Adrenal glands were subjected to morphological analysis to assess lipid droplets content, capsular width, cell proliferation, and steroidogenic proteins expression. The adrenal cortex in untreated SHR showed higher lipid droplet content as than in WKY. In SHR, MRA treatment was associated with higher circulating aldosterone levels and Ki-67 expression in aldosterone-secreting cells. In WKY, the only difference observed after MRA spironolactone treatment was a narrower capsule. There was no difference in abundance of steroidogenic enzyme between groups. In conclusion, MRAs modify adrenal gland function and morphology in SHR. The effects observed within the adrenal glomerulosa with aldosterone-secreting cell proliferation and higher circulating aldosterone levels suggests that MRA treatment provokes activation of the renin angiotensin system. The prognostic value of hyperaldosteronism secondary to MRAs blockade requires further investigation.

Unilateral brain injury to pregnant rats induces asymmetric neurological deficits in the offspring.

Effects of environmental factors may be transmitted to the following generation, and cause neuropsychiatric disorders including depression, anxiety, and posttraumatic stress disorder in the offspring. Enhanced synaptic plasticity induced by environmental enrichment may be also transmitted. We here test the hypothesis that the effects of brain injury in pregnant animals may produce neurological deficits in the offspring. Unilateral brain injury (UBI) by ablation of the hindlimb sensorimotor cortex in pregnant rats resulted in the development of hindlimb postural asymmetry (HL-PA), and impairment of balance and coordination in beam walking test in the offspring. The offspring of rats with the left UBI exhibited HL-PA before and after spinal cord transection with the contralesional (i.e., right) hindlimb flexion. The right UBI caused the offspring to develop HL-PA that however was cryptic and not-lateralized; it was evident only after spinalization, and was characterized by similar occurrence of the ipsi- and contralesional hindlimb flexion. The HL-PA persisted after spinalization suggesting that the asymmetry was encoded in lumbar spinal neurocircuits that control hindlimb muscles. Balance and coordination were affected by the right UBI but not the left UBI. Thus, the effects of a unilateral brain lesion in pregnant animals may be intergenerationally transmitted, and this process may depend on the side of brain injury. The results suggest the existence of left-right side-specific mechanisms that mediate transmission of the lateralized effects of brain trauma from mother to fetus.

Histologic Features of Colon Biopsies (Geboes Score) Associated With Progression of Ulcerative Colitis for the First 36 Months After Biopsy.

BACKGROUND & AIMS: In addition to findings from endoscopy, histologic features of colon biopsies have been associated with outcomes of patients with ulcerative colitis (UC). We investigated associations between Geboes scores (a system to quantify structural changes and inflammatory activity in colon biopsies) and UC progression, and the time period over which this association is valid. METHODS: We analyzed data from 399 asymptomatic patients with UC enrolled in the ACERTIVE study, followed at 13 inflammatory bowel disease (IBD) centers in Portugal through 31 December 2019. Blood and stool samples were collected and analyzed, and all patients underwent sigmoidoscopy within 24 h of sample collection. We assessed baseline endoscopic status (Mayo endoscopic subscore), histologic features of 2 sigmoid and 2 rectal biopsies (Geboes score), and concentration of fecal calprotectin (FC). The primary outcome was UC progression (surgical, pharmacologic, and clinical events). We generated survival curves for 36 months or less and more than 36 months after biopsy according to Geboes score using the Kaplan-Meier method and compared findings with those from a log rank test. Cox regression was adjusted for Mayo endoscopic subscore, Geboes score, and level of FC; results were expressed as adjusted hazard ratios (HR) with 95% CIs. RESULTS: Patients with Geboes scores >2B.0, Geboes scores >3.0, or Geboes scores >4.0 had a higher frequency of, and a shorter time to UC progression, than patients with Geboes scores ≤2B.0, Geboes scores ≤3.0, or Geboes score ≤4.0 (P < .001). Disease progression occurred earlier in patients with Geboes scores >2B.0, Geboes scores >3.0, or Geboes scores >4.0 compared with patients with Geboes scores ≤2B.0 (HR, 2.021; 95% CI, 1.158-3.526), Geboes scores ≤3.0 (HR, 2.007; 95% CI, 1.139-3.534), or Geboes scores ≤4.0 (HR, 2.349; 95% CI, 1.269-4.349), respectively, in the first 36 months after biopsy. Similar results were found for patients with concentrations of FC below 150 µg/g. CONCLUSIONS: We found histologic features of colon biopsies (Geboes score) to be an independent risk factor for progression of UC in the first 36 months after biopsy.

Hindlimb motor responses to unilateral brain injury: spinal cord encoding and left-right asymmetry.

Mechanisms of motor deficits (e.g. hemiparesis and hemiplegia) secondary to stroke and traumatic brain injury remain poorly understood. In early animal studies, a unilateral lesion to the cerebellum produced postural asymmetry with ipsilateral hindlimb flexion that was retained after complete spinal cord transection. Here we demonstrate that hindlimb postural asymmetry in rats is induced by a unilateral injury of the hindlimb sensorimotor cortex, and characterize this phenomenon as a model of spinal neuroplasticity underlying asymmetric motor deficits. After cortical lesion, the asymmetry was developed due to the contralesional hindlimb flexion and persisted after decerebration and complete spinal cord transection. The asymmetry induced by the left-side brain injury was eliminated by bilateral lumbar dorsal rhizotomy, but surprisingly, the asymmetry after the right-side brain lesion was resistant to deafferentation. Pancuronium, a curare-mimetic muscle relaxant, abolished the asymmetry after the right-side lesion suggesting its dependence on the efferent drive. The contra- and ipsilesional hindlimbs displayed different musculo-articular resistance to stretch after the left but not right-side injury. The nociceptive withdrawal reflexes evoked by electrical stimulation and recorded with EMG technique were different between the left and right hindlimbs in the spinalized decerebrate rats. On this asymmetric background, a brain injury resulted in greater reflex activation on the contra- versus ipsilesional side; the difference between the limbs was higher after the right-side brain lesion. The unilateral brain injury modified expression of neuroplasticity genes analysed as readout of plastic changes, as well as robustly impaired coordination of their expression within and between the ipsi- and contralesional halves of lumbar spinal cord; the effects were more pronounced after the left side compared to the right-side injury. Our data suggest that changes in the hindlimb posture, resistance to stretch and nociceptive withdrawal reflexes are encoded by neuroplastic processes in lumbar spinal circuits induced by a unilateral brain injury. Two mechanisms, one dependent on and one independent of afferent input may mediate asymmetric hindlimb motor responses. The latter, deafferentation resistant mechanism may be based on sustained muscle contractions which often occur in patients with central lesions and which are not evoked by afferent stimulation. The unusual feature of these mechanisms is their lateralization in the spinal cord.

IL-4/IFN-γ inflammatory cytokine profile induces a deficient regulation of the IL-1ß/IL-1RI/EP2/COX-2 pathway in nasal mucosa.

BACKGROUND: We hypothesized that the peculiar mixed interleukin-4 (IL-4/Th2) and interferon gamma INF-γ (INF-γ/Th1) inflammatory milieu found in the airways of patients with aspirin-exacerbated respiratory disease (AERD) is responsible for the altered regulation of the IL-1ß/IL-1RI-/EP2/COX-2 autocrine loop also found in these patients. The objective of the study is to demonstrate that IL-4 and INF-γ cytokines, are capable of inducing in healthy nasal mucosa (NM) the dysregulation of the autocrine loop of COX reported in AERD. SUBJECTS AND METHODS: Fibroblasts were obtained from NM (n = 8). To evaluate the role of IL-4 and IFN-γ on the autocrine loop, fibroblasts were incubated with or without IL-1ß, in the presence or absence of IL-4 and/or IFN-γ for 48 h. After this period, the expression of EP2, EP3, EP4, IL-1RI, COX-2 and mPGES-1 was measured by Western blot. RESULTS: Stimulation of fibroblasts with IL-1ß significantly increased the expression of EP2, but had no effects on EP3 and EP4 expression Incubation with IL-4 or IFN-γ alone was not able to modify the expression of any of the components of the autocrine loop. In contrast, co-treatment with IL-4 and IFN-γ was able to significantly inhibit IL-1ß-induced EP2, IL-1RI, COX-2 and mPGES-1. CONCLUSION: These results suggest that the mixed Th1/Th2 inflammatory pattern found in the airways of AERD patients might be responsible for the altered regulation of the COX pathway also reported in these asthma patients.

Miliary Tuberculosis in a Crohn's Disease Patient: The Risk beyond the Screening.

Tumor necrosis factor alpha (TNFα) antagonist is recognized as an effective treatment to achieve clinical remission and healing mucosal in patients with moderate to severe active Crohn's disease. Considering that it plays a central role in immune-mediated modulation, there are some obvious concerns about its long-term safety. There is evidence that it may increase the risk of opportunistic infections such as tuberculosis, particularly reactivation of previous latent infection. Due to the global high incidence of tuberculosis and its frequent severity in immunocompromised patients, the exclusion of latent infection is currently part of the screening prior to anti-TNFα therapy. Only a few cases of life-threatening disseminated tuberculosis have been reported in immunocompromised patients probably related to widespread use of higher-accuracy screening tests, such as interferon-γ release assays. However, despite negative screening, the risk of active tuberculosis infection remains during treatment. In that instance, tuberculosis infection becomes considerably more difficult to diagnose due to its altered pattern presentation (extrapulmonary and disseminated infection) and is harder to treat because of the high rate of resistance and its associated relevant morbidity and mortality. We report an enigmatic case of a miliary tuberculosis despite negative latent infection screening, using interferon-γ release assays, in a Crohn's disease patient undergoing treatment with infliximab and azathioprine, focusing on the screening and diagnostic and therapeutic challenge. This case enhances the awareness of anti-TNFα therapy management and the need for strategies to diagnose and treat tuberculosis in this context.

Os antagonistas do factor de necrose tumoral alfa são reconhecidos como eficazes na obtenção de remissão clínica e cicatrização da mucosa na doença de Crohn ativa moderada a grave. Considerando que estes desempenham um papel central na modulação imunomediada, há alguma preocupação sobre a sua segurança a longo prazo. Assim, existe evidência de que podem aumentar o risco de infeções oportunistas, como a tuberculose, em particular a reativação da infeção latente. Devido à elevada incidência mundial de tuberculose e à sua frequência em doentes imunocomprometidos, a exclusão da infeção latente faz parte do rastreio antes de iniciar anti-TNFα. Apenas alguns casos de tuberculose disseminada grave foram relatados em doentes imunocomprometidos, provavelmente relacionados com o uso generalizado de testes de rastreio de maior acuidade, como os ensaios de libertação de interferão gama. No entanto, apesar do rastreio negativo, o risco de desenvolver infeção ativa por tuberculose permanece durante o tratamento. Nestes casos, a tuberculose torna-se mais difícil de diagnosticar, devido à sua forma de apresentação mais rara (infeção extrapulmonar e disseminada), é mais difícil de tratar, devido à alta taxa de resistência e apresenta maior morbidade e mortalidade associada. Os autores relatam um caso enigmático de tuberculose miliar, apesar do rastreio negativo de infeção latente, através de ensaio de libertação de interferão gama, em doente com Crohn tratado com infliximab e azatioprina, com foco no rastreio, diagnóstico e desafio terapêutico. Este caso levanta a discussão o manejo da terapêutica anti-TNFα e a necessidade de se desenvolverem estratégias para diagnosticar e tratar precocemente a tuberculose neste contexto.

Mixed cryoglobulinemia: a diagnostic and therapeutic challenge.

Mixed cryoglobulinemia is frequently secondary to hepatitis C virus infection. Diagnosis and therapeutic management are challenging, depending on the spectrum and severity of manifestations, as well as on the presence of comorbidities. We describe a case of a 79-year-old woman with a non-cirrhotic hepatitis C virus infection presenting with weakness, arthralgias, purpuric rash with left leg ulcerative lesions, bilateral peripheral sensorimotor polyneuropathy, renal impairment and cardiac failure. The investigation was compatible with a severe type II mixed cryoglobulinemia with multisystemic involvement, including a low-grade B cell lymphoma and concomitant intestinal tuberculosis. Initial management with immunosuppressive therapy with glucocorticoids to control symptoms and simultaneous tuberculosis treatment was required. Unavailability of adequate antiviral treatment led to the need to control the severity of systemic manifestations with rituximab, before the effective aetiological treatment with sofosbuvir and ledipasvir was possible, allowing the definitive resolution of the disease.