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Purpose: This report highlights a rare case of delayed manifestation of proliferative retinopathy associated with chronic myeloid leukemia (CML) during remission. Observations: Case report and review of the literature; In this case report, we outline the delayed manifestation and clinical progression of proliferative retinopathy in a 52-year-old male patient with a history of CML diagnosed in 2001. Initially, the patient presented with a white blood cell count (WBC) of 402,200/µl, and the leukocytosis persisted until 2005. Thereafter, the patient remained in remission for over 15 years without any visual complaints until 2022. At that time, the patient sought medical attention due to a ten-day history of left eye visual impairment, leading to the discovery of peripheral neovascularization in both eyes and vitreous hemorrhage in the left eye during fundus examination. The WBC count at the time of presentation to the Emergency Department was 10,460/µl. The patient was treated with fluorescein angiography guided panretinal photocoagulation to the areas of ischemic retina. Subsequent follow-up after eight months demonstrated regression of neovascularization. Conclusions and Importance: Our findings highlight the occurrence of proliferative retinopathy in the context of CML, uniquely manifesting during remission. This case emphasizes the importance of ophthalmological assessments not only at the time of CML diagnosis but also during subsequent follow-ups, recognizing the potential for delayed presentation of ocular complications.
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More frequent among adults, phenocopies may be caused by somatic mutations or anti-cytokine autoantibodies, mimicking the phenotypes of primary immunodeficiencies. A fourteen-year-old girl was referred for a two-year history of weight loss and multiple recurrent abscesses, complicated recurrent pneumonia, pyelonephritis, osteomyelitis, and septic shock, without fever. She had started with nausea, hyporexia, and weight loss, then with abscesses in her hands, knee, ankle, and spleen. She also developed a rib fracture and left thoracic herpes zoster. The patient was cachectic, with normal vital signs, bilateral crackles on chest auscultation, tumefaction of the knee joint, and poorly healed wounds in hands and chest, oozing a yellowish fluid. Chest computed tomography revealed multiple bilateral bronchiectases. Laboratory workup reported chronic anemia, leukocytosis, neutrophilia, mild lymphopenia, thrombocytosis, pan-hypergammaglobulinemia, and elevated acute serum reactants. Lymphocyte subsets were low but present. Mycobacterium tuberculosis was detected via polymerase chain reaction in a bone biopsy specimen from ankle osteomyelitis. Whole-exome sequencing failed to identify a monogenic defect. Interleukin-12 was found markedly elevated in the serum of the patient. Phosphorylation of STAT4, induced by increasing doses of IL-12, was neutralized by patient serum, confirming the presence of anti-IL12 autoantibodies. IL-12 and IL-23 are crucial cytokines in the defense against intracellular microorganisms, the induction of interferon-gamma production by lymphocytes, and other inflammatory functions. Patients who develop neutralizing serum autoantibodies against IL12 manifest late in life with weight loss, multiple recurrent abscesses, poor wound healing, and fistulae. Treatment with anti-CD20 monoclonal antibodies was effective.
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Abscesso , Autoanticorpos , Humanos , Feminino , Autoanticorpos/imunologia , Autoanticorpos/sangue , Adolescente , Abscesso/imunologia , Subunidade p40 da Interleucina-12/imunologia , Recidiva , Osteomielite/imunologiaRESUMO
This study aimed to analyze the prevalence, sociobehavioral factors and clinical-laboratory consequences of late presentation among people living with HIV (PLHIV) in the Brazilian Amazon region. In total, 402 HIV + individuals treated at reference units in Belém city (Pará, Brazil) between 2018 and 2019 were evaluated. Late presentation was defined as a first-collection LTCD4+ count below 350 cells/µL. Sociodemographic, behavioral and clinical data were obtained from questionnaires or medical records. Th1, Th2 and Th17 cytokine profiles were evaluated by flow cytometry. Longitudinal data on viral load, T lymphocytes, and antiretroviral therapy administration were obtained from control and logistic databases. Approximately 52.73% of the participants were late presenters and sought medical care 7-12 + months after their primary HIV diagnosis. Sociobehavioral factors associated with late presentation included illicit drug use for more than 5 years, polyamory, no alcohol consumption, homosexuality, and sexual inactiveness after HIV diagnosis. Clinically, late presentation was associated with coinfection rate; polysymptomatology; high IFN-É£, IL-6 and IL-10 levels; nonresponse to antiretroviral therapy; and virological failure- and tuberculosis coinfection-motivated changes to therapy. In summary, the prevalence of late presentation in Pará in the Brazilian Amazon region is high. Delays in seeking specialized care after a primary HIV diagnosis cause medium/long-term changes in the life expectancy and health of PLHIV.
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Infecções por HIV , Carga Viral , Humanos , Brasil/epidemiologia , Infecções por HIV/tratamento farmacológico , Infecções por HIV/epidemiologia , Infecções por HIV/psicologia , Masculino , Feminino , Adulto , Fatores de Risco , Pessoa de Meia-Idade , Prevalência , Contagem de Linfócito CD4 , Diagnóstico Tardio , Comportamento Sexual , Estudos Transversais , Coinfecção/epidemiologia , Fármacos Anti-HIV/uso terapêuticoRESUMO
Introducción: Los pacientes con lupus eritematoso sistémico (LES) diagnosticados después de los 50 años presentan una enfermedad menos severa y un curso clínico más leve. El objetivo de este estudio es describir las características clínicas y de laboratorios del LES en pacientes de edad avanzada. Material y Método: Estudio observacional, descriptivo, de corte trasverso, retrospectivo, de pacientes con el diagnóstico de LES, de inicio posterior a los 50 años de edad, que consultaron en el Hospital Nacional, en el periodo comprendido entre diciembre de 2016 y mayo de 2024. Resultados: Se estudiaron 30 pacientes entre 51 y 87 años (edad media: 62,5 años ± 8,5), 16 mujeres (53,3%) y 14 varones 14 (46,6 %). El tiempo de enfermedad previo al diagnóstico fue de 59,4 ± 8.3 (50-80) días. La duración de la enfermedad fue en promedio 5 años ± 5,1 (1-26). Las principales manifestaciones clínicas fueron las artralgias 26 (86,6%), artritis 22 (72,3%), pérdida de peso 10 (33,3%) y fiebre prolongada (30%). Presentaron comorbilidades 19 pacientes (63,3 %), siendo la hipertensión arterial la principal. El anti-DNA fue positivo en 12 pacientes (42,8%), el anti-Ro en 5/25 pacientes (20%), el anti-Sm en 2/26 (7,9%). La eritrosedimentación en la primera hora fue ≥ 20 mm en 17/23 (73,9%). El 100% recibió tratamiento con hidroxicloroquina, mientras que recibieron corticoides 26 (86.6%) pacientes, micofenolato mofetil 7 (24,4%), ciclofosfamida 4 (13,3%). La mortalidad fue del 6,6 %. Conclusión: Los principales hallazgos fueron artralgias y artritis, siendo menos frecuentes los casos graves. La mayoría presentó comorbilidades, siendo la hipertensión arterial la más frecuente. La mortalidad fue del 6,6% de causa cardiovascular.
Introduction: Patients with systemic lupus erythematosus (SLE) diagnosed after the age of 50 have a less severe disease and a milder clinical course. The objective of this study is to describe the clinical and laboratory characteristics of SLE in elderly patients. Material and Method: Observational, descriptive, cross-sectional, retrospective study of patients with the diagnosis of SLE, with onset after 50 years of age, evaluated at the National Hospital, in the period between December 2016 and May of 2024. Results: 30 patients between 51 and 87 years old (mean age: 62.5 years ± 8.5) were studied, 16 women (53.3%) and 14 men (46.6%). The time to diagnosis was 59.4 ± 8.3 (50-80) days. The duration of the disease was on average 5 years ± 5.1 (1-26). The main clinical manifestations were arthralgia in 26 (86.6%), arthritis in 22 (72.3%), weight loss in 10 (33.3%) and prolonged fever (30%). Nineteen patients (63.3%) had comorbidities, the main one being high blood pressure. Anti-dsDNA was positive in 12 patients (42.8%), anti-Ro in 5/25 patients (20%), anti-Sm in 2/26 (7.9%). The erythrocyte sedimentation rate was ≥ 20 mm in 17/23 (73.9%). All patients were treatment with hydroxychloroquine, 26 (86.6%) patients received corticosteroids, 7 (24.4%) mycophenolate mofetil, 4 (13.3%) cyclophosphamide. Mortality was 6.6%. Conclusion: The main findings were arthralgia and arthritis, with severe cases being less frequent. The majority presented comorbidities, with high blood pressure being the most common. Mortality was 6.6% due to cardiovascular causes.
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The evolution of new variants of plant pathogens is one of the biggest challenges to controlling and managing plant diseases. Of the forces driving these evolutionary processes, global migration events are particularly important for widely distributed diseases such as potato late blight, caused by the oomycete Phytophthora infestans. However, little is known about its migration routes outside North America and Europe. This work used genotypic data from population studies to elucidate the migration history originating the Colombian P. infestans population. For this purpose, a dataset of 1,706 P. infestans genotypes was recollected, representing North and South America, Europe, and Asia. Descriptive analysis and historical records from North America and Europe were used to propose three global migration hypotheses, differing on the origin of the disease (Mexico or Peru) and the hypothesis that it returned to South America from Europe. These scenarios were tested using approximate Bayesian computation. According to this analysis, the most probable scenario (posterior probability = 0.631) was the one proposing a Peruvian origin for P. infestans, an initial migration toward Colombia and Mexico, and a later event from Mexico to the United States and then to Europe and Asia, with no return to northern South America. In Colombia, the scenario considering a single migration from Peru and posterior migrations within Colombia was the most probable, with a posterior probability of 0.640. The obtained results support the hypothesis of a Peruvian origin for P. infestans followed by rare colonization events worldwide.
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Phytophthora infestans , Doenças das Plantas , Phytophthora infestans/genética , Colômbia , Doenças das Plantas/microbiologia , Genótipo , Teorema de Bayes , Solanum tuberosum/microbiologia , Europa (Continente) , México , Ásia , América do NorteRESUMO
BACKGROUND: Infant mortality in French Guiana, a French overseas territory, is 2.7 times greater than in mainland France. Given the importance of better understanding infant mortality we aimed to describe the early & late neonatal, and postneonatal mortality in French Guiana between 2007 and 2022. METHODS: We used data from the Institut National de la Statistique et des Etudes Economiques to describe trends and performed survival analysis. RESULTS: Overall, there were 1 073 deaths before one year of age, of which 297 (27.7 %) occurred on the first day of life. The overall proportion of early neonatal deaths was 47.1 %, late neonatal deaths was 17.3 %, and post-neonatal deaths was 35.6 %. The overall incidences were 4.6 per 1,000 for early neonatal mortality, 1.4 per 1,000 for late neonatal mortality, and 3.1 per 1,000 for post neonatal mortality. The incidence for infant mortality for French Guiana residents was thus 9.1 per 1,000. CONCLUSIONS: We show that post neonatal deaths in French Guiana are proportionally greater than in mainland France and they do not seem to decline, as they did in France. The relative proportions of post-neonatal mortality can thus help to identify important areas for action to correct excess infant mortality. Although poor pregnancy follow-up remains a problem we show that follow-up of infants is also a pressing problem that warrants increased efforts.
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Mortalidade Infantil , Humanos , Guiana Francesa/epidemiologia , Mortalidade Infantil/tendências , Recém-Nascido , Lactente , Feminino , Masculino , Análise de Sobrevida , IncidênciaRESUMO
Background: The short-term complications from chimeric antigen receptor T-cell therapy (CART) are well characterized, but the long-term complications still need to be further investigated. Therefore, herein, we will review the currently available literature published on the late adverse events following CART. Methods: We reviewed published data available from pivotal trials and real-world experiences with anti-CD19 CART (CART19) for adults with lymphoma. We defined late events as occurring or persisting beyond 1 month after CART infusion. We focused our literature review on the following late-event outcomes post-CART19: cytopenia, immune reconstitution, infections, and subsequent malignancies. Results: Grade 3-4 cytopenia beyond 30 days occurs in 30%-40% of patients and beyond 90 days in 3%-22% of patients and is usually managed with growth-factor and transfusion support, along with neutropenic prophylaxis. B-cell aplasia and hypogammaglobulinemia are expected on-target off-tumor effects of CART19, 44%-53% of patients have IgG < 400 mg/dL, and approximately 27%-38% of patients receive intravenous immunoglobulin (IVIG) replacement. Infections beyond the initial month from CART19 are not frequent and rarely severe, but they are more prevalent and severe when patients receive subsequent therapies post-CART19 for their underlying disease. Late neurotoxicity and neurocognitive impairment are uncommon, and other causes should be considered. T-cell lymphoma (TCL) after CART is an extremely rare event and not necessarily related to CAR transgene. Myeloid neoplasm is not rare post-CART, but unclear causality given heavily pretreated patient population is already at risk for therapy-related myeloid neoplasm. Conclusion: CART19 is associated with clinically significant long-term effects such as prolonged cytopenia, hypogammaglobulinemia, and infections that warrant clinical surveillance, but they are mostly manageable with a low risk of non-relapse mortality. The risk of subsequent malignancies post-CART19 seems low, and the relationship with CART19 and/or prior therapies is unclear; but regardless of the possible causality, this should not impact the current benefit-risk ratio of CART19 for relapsed/refractory B-cell non-Hodgkin lymphoma (NHL).
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Early-onset Alzheimer's disease (EOAD), defined as Alzheimer's disease onset before 65 years of age, has been significantly less studied than the "classic" late-onset form (LOAD), although EOAD often presents with a more aggressive disease course, caused by variants in the APP, PSEN1, and PSEN2 genes. EOAD has significant differences from LOAD, including encompassing diverse phenotypic manifestations, increased genetic predisposition, and variations in neuropathological burden and distribution. Phenotypically, EOAD can be manifested with non-amnestic variants, sparing the hippocampi with increased tau burden. The aim of this article is to review the different genetic bases, risk factors, pathological mechanisms, and diagnostic approaches between EOAD and LOAD and to suggest steps to further our understanding. The comprehension of the monogenic form of the disease can provide valuable insights that may serve as a roadmap for understanding the common form of the disease.
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Resumen Introducción : La población de niños que comienzan con lentitud el desarrollo del lenguaje varía amplia mente, tanto en su perfil inicial como en la respuesta a la intervención. En este sentido, existe un grupo de niños, denominados hablantes tardíos, que continúan mostrando dificultades persistentes en el lenguaje. Al gunos de estos niños muestran signos compatibles con la dispraxia verbal, y que se ponen de manifiesto a lo largo de la intervención. Método : En este trabajo presentamos la diferente respuesta a la intervención de dos perfiles de hablante tardío. Concretamente, se aplicó el programa Target Word©, del centro Hanen, que conjuga la técnica de la estimulación focalizada con la orientación a padres so bre estrategias que promueven el desarrollo del lenguaje. Resultados : Gran parte de la sintomatología mostrada en uno de los dos casos, que experimentó un progreso pobre, coincide con las descripciones retrospectivas de niños posteriormente diagnosticados con dispraxia y pueden considerarse indicadores tempranos del trastor no: ininteligibilidad, inventario consonántico reducido o dificultades en la repetición de palabras. Discusión : La diferente respuesta a la intervención contribuye a la toma de decisiones diagnósticas y a la aplicación temprana de estrategias específicas para la mejora de las habilidades de aprendizaje del habla me diante la incorporación de los principios del aprendizaje motor. Los escasos estudios de intervención en casos de sospecha de dispraxia verbal en la infancia temprana ofrecen resultados prometedores en diversos indicadores de evaluación del habla, y proporcionan a los profesio nales una información valiosa en la que fundamentar la intervención en esta población.
Abstract Introduction : The population of children with slow emergence of language development varies widely, both in their initial profile and in their response to interven tion. In this sense, there is a group of late talkers who continue to show persistent language difficulties, in some cases exhibiting signs compatible with verbal dyspraxia. Method : In this paper we present the different response to intervention of two profiles of late talk ers. Specifically, the Target Word© program (Hanen Centre) was implemented, which is addressed to late-talking children and their families. It combines the technique of focused stimulation with guidance to parents on strategies that stimulate global language development. Results : Much of the symptomatology shown in one case of poor progress coincides with retrospective de scriptions of children subsequently diagnosed with dyspraxia and can be considered early indicators of the disorder: unintelligibility, reduced consonant inventory or difficulties in word repetition. Discussion : The different response to intervention contributes to diagnostic decision making and the early implementation of specific strategies directed to improve speech learning skills by incorporating motor learning principles. The few studies of intervention in suspected verbal dyspraxia in early childhood offer promising re sults on a variety of speech assessment indicators, and provide practitioners with valuable information with which to support the intervention in this population.
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PURPOSE: Radiotherapy (RT) with concomitant cisplatin (CRT) or cetuximab (ERT) are accepted treatment options for locally advanced squamous cell carcinoma of the head and neck (LA-SCCHN). Long-term adverse events (AEs) have a vast impact on patients' quality of life. This study explored tissue biomarkers which could help predict late toxicity. METHODS/PATIENTS: Single-institution prospective study including patients aged ≥ 18 with histologically confirmed newly diagnosed LA-SCCHN treated with RT and either concomitant cisplatin q3w or weekly cetuximab, according to institutional protocols. All patients underwent pre- and post-treatment skin biopsies of neck regions included in the clinical target volume. Angiogenesis, macrophages, and extracellular matrix (ECM) markers were evaluated by immunohistochemistry (IHC). RESULTS: From April 15, 2016, to December 11, 2017; 31 patients were evaluated [CRT = 12 (38.7%) and ERT = 19 (61.3%)]. 27 patients (87%) had received induction chemotherapy. All patients finished RT as planned. IHC expression of vasculature (CD34) and collagen (Masson's Trichrome) did not differ significantly between and within CRT and ERT arms. Conversely, an increased CD68 and CD163 macrophage infiltration expression was observed after treatment, without significant impact of treatment modality. Patients with higher late toxicity showed lower expression of macrophage markers in pre-treatment samples compared with those with lower late toxicity, with statistically significant differences for CD68. CONCLUSIONS: Angiogenesis and ECM biomarkers did not differ significantly between CRT and ERT. Macrophage markers increased after both treatments and deserve further investigation as predictors of late toxicity in LA-SCCHN patients. [Protocol code: TOX-TTCC-2015-01/Spanish registry of clinical studies (REec): 2015-003012-21/Date of registration: 27/01/2016].
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Background: Orbital hypertelorism is a rare congenital condition caused by craniofacial malformations. It consists of complete orbital lateralization, characterized by an increase in distance (above the 95th percentile) of the inner canthal (ICD), outer canthal, and interpupillary distances. It can be approached surgically, and the main techniques are box osteotomy and facial bipartition. The surgical procedure is usually performed before the age of 8. We describe here two patients who underwent late surgical correction using the box osteotomy technique. Case Description: Patient 1: A 13-year-old female presenting isolated hypertelorism with 5 cm ICD and left eye amblyopia. Patient 2: A 15-year-old female with orbital hypertelorism, 4.6 cm ICD, and nasal deformity. Both patients underwent orbital translocation surgery and had no neurological disorders. Conclusion: The article reports two cases of isolated hypertelorism treated late with the box osteotomy technique. Both surgeries were successful, with no postoperative complications. It appears that it is possible to obtain good surgical results even in patients who have not been able to undergo surgery previously.
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The study of thirty-two shed crowns from the Portezuelo Formation (middle Turonian-late Coniacian) at the Sierra del Portezuelo locality, reveals six distinct tooth morphotypes identified through cladistic, discriminant, and cluster analyses. Two morphotypes were identified as belonging to Megaraptoridae, three to Abelisauridae, one to Abelisauroidea, and one to Alvarezsauridae. Additionally, two of the morphotypes exhibit a combination of dental features typically found in megaraptorid and abelisauridtheropods. These results suggest a greater diversity of theropods in the original ecosystem than previously thought, including the presence of a second morphotype of megaraptorid and alvarezsaurid previously undocumented in this formation. Furthermore, the existence of Morphotype 6 indicates the potential coexistence of medium-sized abelisauroids alongside larger abelisaurids in the same ecosystem. These findings underscore the importance of future expeditions to the Sierra del Portezuelo locality to further our understanding of these previously unknown theropod species.
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Fósseis , Dente , Animais , Dente/anatomia & histologia , Biodiversidade , Argentina , FilogeniaRESUMO
La varicela es una infección poco frecuente durante la gestación, el riesgo para el feto y las manifestaciones clínicas, variarán en función del momento del embarazo en que se produce la infección materna, cuando la erupción maculopapular materna se produce entre los 5 días previos al parto y las 48 horas posteriores, se habla de varicela neonatal tardía. La clínica es grave, con afectación visceral (pulmonar, cerebral, hepática, hemorragias cutáneas, etc.) y un 30 % de los casos desarrollarán una varicela fulminante. Se presenta el caso de neonato masculino que consultó por lesiones en piel, tipo pápulas eritematosas y vesiculares pleomorfas, de distribución dispersa. Con evolución clínica tórpida, permaneció 24 horas en la institución, con franco deterioro respiratorio y neurológico, compatible con cuadro de varicela neonatal tardía fulminante(AU)
Chickenpox is considered a rare infection during pregnancy, the risk to the fetus and the clinical manifestations will vary depending on the time of pregnancy when the maternal infection occurs, when the maternal maculo-papular injuries occurs within the previous 5 days after delivery and 48 hours after, there is talk of late neonatal chickenpox. The symptoms are severe with visceral involvement (lung, brain, liver, skin bleeding, etc.) and 30% of cases will develop fulminant chickenpox. We present the case of a male neonate who consults due to skin lesions, such as erythematous papules and pleomorphic vesicles, with scattered distribution. With a torpid clinical course, who remains in the institution for 24 hours, with frank respiratory and neurological deterioration compatible with late-neonatal fulminant varicella symptoms(AU)
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Humanos , Masculino , Recém-Nascido , Varicela , Herpesvirus Humano 3RESUMO
OBJECTIVE: The objective of this study was to examine the association of cardiorespiratory events, including apnea, periodic breathing, intermittent hypoxemia (IH), and bradycardia, with late-onset sepsis for extremely preterm infants (<29 weeks of gestational age) on vs off invasive mechanical ventilation. STUDY DESIGN: This is a retrospective analysis of data from infants enrolled in Pre-Vent (ClinicalTrials.gov identifier NCT03174301), an observational study in 5 level IV neonatal intensive care units. Clinical data were analyzed for 737 infants (mean gestational age: 26.4 weeks, SD 1.71). Monitoring data were available and analyzed for 719 infants (47 512 patient-days); of whom, 109 had 123 sepsis events. Using continuous monitoring data, we quantified apnea, periodic breathing, bradycardia, and IH. We analyzed the relationships between these daily measures and late-onset sepsis (positive blood culture >72 hours after birth and ≥5-day antibiotics). RESULTS: For infants not on a ventilator, apnea, periodic breathing, and bradycardia increased before sepsis diagnosis. During times on a ventilator, increased sepsis risk was associated with longer events with oxygen saturation <80% (IH80) and more bradycardia events before sepsis. IH events were associated with higher sepsis risk but did not dynamically increase before sepsis, regardless of ventilator status. A multivariable model including postmenstrual age, cardiorespiratory variables (apnea, periodic breathing, IH80, and bradycardia), and ventilator status predicted sepsis with an area under the receiver operator characteristic curve of 0.783. CONCLUSION: We identified cardiorespiratory signatures of late-onset sepsis. Longer IH events were associated with increased sepsis risk but did not change temporally near diagnosis. Increases in bradycardia, apnea, and periodic breathing preceded the clinical diagnosis of sepsis.
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Apneia , Bradicardia , Hipóxia , Lactente Extremamente Prematuro , Sepse , Humanos , Bradicardia/epidemiologia , Bradicardia/etiologia , Apneia/epidemiologia , Estudos Retrospectivos , Recém-Nascido , Hipóxia/complicações , Feminino , Masculino , Sepse/complicações , Sepse/epidemiologia , Doenças do Prematuro/epidemiologia , Doenças do Prematuro/diagnóstico , Respiração Artificial , Unidades de Terapia Intensiva Neonatal , Idade GestacionalRESUMO
The fossil fish Ptychodus Agassiz, 1834, characterized by a highly distinctive grinding dentition and an estimated gigantic body size (up to around 10 m), has remained one of the most enigmatic extinct elasmobranchs (i.e. sharks, skates and rays) for nearly two centuries. This widespread Cretaceous taxon is common in Albian to Campanian deposits from almost all continents. However, specimens mostly consist of isolated teeth or more or less complete dentitions, whereas cranial and post-cranial skeletal elements are very rare. Here we describe newly discovered material from the early Late Cretaceous of Mexico, including complete articulated specimens with preserved body outline, which reveals crucial information on the anatomy and systematic position of Ptychodus. Our phylogenetic and ecomorphological analyses indicate that ptychodontids were high-speed (tachypelagic) durophagous lamniforms (mackerel sharks), which occupied a specialized predatory niche previously unknown in fossil and extant elasmobranchs. Our results support the view that lamniforms were ecomorphologically highly diverse and represented the dominant group of sharks in Cretaceous marine ecosystems. Ptychodus may have fed predominantly on nektonic hard-shelled prey items such as ammonites and sea turtles rather than on benthic invertebrates, and its extinction during the Campanian, well before the end-Cretaceous crisis, might have been related to competition with emerging blunt-toothed globidensine and prognathodontine mosasaurs.
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Fósseis , Filogenia , Tubarões , Animais , Fósseis/anatomia & histologia , México , Tubarões/anatomia & histologia , Tubarões/classificação , Tubarões/fisiologia , Evolução Biológica , Dente/anatomia & histologiaRESUMO
PURPOSE OF REVIEW: Time-restricted eating (TRE), a form of intermittent fasting, restricts feeding time across the day, imposing a daily 'eating window'. The time of day when the eating window occurs could result in differential metabolic effects. Here, we describe recent intervention studies in humans assessing the metabolic consequences of an early- (i.e., eating window starting in the early morning) vs. late (i.e., eating window starting after midday)-TRE protocol. RECENT FINDINGS: Well-controlled studies indicate that both TRE protocols effectively reduce body weight and improve altered glucose metabolism, lipid profile, inflammation, or blood pressure levels. An early-TRE (e-TRE) might have a further positive impact on improving blood glucose, insulin levels, and insulin resistance. However, the studies directly assessing the metabolic consequences of an early- vs. late-TRE have shown dissimilar findings, and more well-controlled clinical trials are needed on the metabolic benefits of these two types of TRE. Evidence suggests that an e-TRE might have enhanced metabolic results, particularly regarding glucose homeostasis. More long-term studies, including larger sample sizes, are needed to assess the metabolic, circadian, and adherence benefits, together with socio-cultural acceptance of both TRE approaches.
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Glicemia , Jejum , Resistência à Insulina , Humanos , Glicemia/metabolismo , Fatores de Tempo , Insulina/sangue , Pressão Sanguínea , Redução de Peso , Peso CorporalRESUMO
The pathophysiology of many neuropsychiatric disorders is still poorly understood. Identification of biomarkers for these diseases could benefit patients due to better classification and stratification. Exosomes excreted into the circulatory system can cross the blood-brain barrier and carry a cell type-specific set of molecules. Thus, exosomes are a source of potential biomarkers for many diseases, including neuropsychiatric disorders. Here, we investigated exosomal proteins produced from human-induced pluripotent stem cells (iPSCs) and iPSC-derived neural stem cells, neural progenitors, neurons, astrocytes, microglia-like cells, and brain capillary endothelial cells. Of the 31 exosome surface markers analyzed, a subset of biomarkers were significantly enriched in astrocytes (CD29, CD44, and CD49e), microglia-like cells (CD44), and neural stem cells (SSEA4). To identify molecular fingerprints associated with disease, circulating exosomes derived from healthy control (HC) individuals were compared against schizophrenia (SCZ) patients and late-onset Alzheimer's disease (LOAD) patients. A significant epitope pattern was identified for LOAD (CD1c and CD2) but not for SCZ compared to HC. Thus, analysis of cell type- and disease-specific exosome signatures of iPSC-derived cell cultures may provide a valuable model system to explore proteomic biomarkers for the identification of novel disease profiles.
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Vesículas Extracelulares , Células-Tronco Pluripotentes Induzidas , Humanos , Células Endoteliais , Proteômica , EncéfaloRESUMO
OBJECTIVES: When rheumatoid arthritis (RA) starts after the age of 60 it is called elderly-onset rheumatoid arthritis (EORA) and when it starts earlier, young-onset rheumatoid arthritis. (YORA). There are few Latin American studies that compared both groups. The objective of the study was to evaluate differences in the clinical characteristics, evolution and treatment among patients with RA with onset before or after 60 years of age. MATERIALS AND METHODS: Observational study of patients with RA attended consecutively in four centers in Argentina. Sociodemographic data, comorbidities, clinical manifestations at diagnosis, presence of rheumatoid factor and/or anti-CCP (cyclic citrullinated peptide) and treatments received were collected. At the last visit, swollen and tender joints, assessment of disease activity by the patient and physician, the presence of radiographic erosions, and functional status using the HAQ-DI were recorded. RESULTS: 51 patients from each group were analyzed. The EORA group had a significantly higher proportion of smokers (58.8% vs. 35.3%, pâ¯=â¯0.029), cardiovascular history (54.9% vs. 21.6%, pâ¯=â¯0.001), abrupt onset (49% vs. 29.4%, pâ¯=â¯0.034) or with symptoms similar to PMR (19.6% vs. 0%, pâ¯=â¯0.001). Lower methotrexate doses were used in the EORA group: 19â¯mg (15-25) vs. 21.9â¯mg (20-25) (pâ¯=â¯0.0036) and more frequently did not receive bDMARDs or tsDMARDs. DISCUSSION AND CONCLUSIONS: The benefits of intensive treatment in patients with RA have been described. In this study, the use of DMARDs in the EORA group was less intensive, suggesting that advanced age constitutes a barrier in the therapeutic choice.
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Antirreumáticos , Artrite Reumatoide , Idoso , Humanos , Artrite Reumatoide/tratamento farmacológico , Fator Reumatoide , Metotrexato/uso terapêutico , Anticorpos Antiproteína Citrulinada , Antirreumáticos/uso terapêuticoRESUMO
Between 2016 and 2018, Brazil experienced major sylvatic yellow fever (YF) outbreaks that caused hundreds of casualties, with Minas Gerais (MG) being the most affected state. These outbreaks provided a unique opportunity to assess the immune response triggered by the wild-type (WT) yellow fever virus (YFV) in humans. The plaque reduction neutralization test (PRNT) is currently the standard method to assess the humoral immune response to YFV by measuring neutralizing antibodies (nAbs). The present study aimed to evaluate the humoral immune response of patients from the 2017-2018 sylvatic YF outbreak in MG with different disease outcomes by using PRNTs with a WT YFV strain, isolated from the 2017-2018 outbreak, and a vaccine YFV strain. Samples from naturally infected YF patients were tested, in comparison with healthy vaccinees. Results showed that both groups presented different levels of nAb against the WT and vaccine strains, and the levels of neutralization against the strains varied homotypically and heterotypically. Results based on the geometric mean titers (GMTs) suggest that the humoral immune response after a natural infection of YFV can reach higher levels than that induced by vaccination (GMT of patients against WT YFV compared to GMT of vaccinees, P < 0.0001). These findings suggest that the humoral immune responses triggered by the vaccine and WT strains of YFV are different, possibly due to genetic and antigenic differences between these viruses. Therefore, current means of assessing the immune response in naturally infected YF individuals and immunological surveillance methods in areas with intense viral circulation may need to be updated.IMPORTANCEYellow fever is a deadly febrile disease caused by the YFV. Despite the existence of effective vaccines, this disease still represents a public health concern worldwide. Much is known about the immune response against the vaccine strains of the YFV, but recent studies have shown that it differs from that induced by WT strains. The extent of this difference and the mechanisms behind it are still unclear. Thus, studies aimed to better understand the immune response against this virus are relevant and necessary. The present study evaluated levels of neutralizing antibodies of yellow fever patients from recent outbreaks in Brazil, in comparison with healthy vaccinees, using plaque reduction neutralization tests with WT and vaccine YFV strains. Results showed that the humoral immune response in naturally infected patients was higher than that induced by vaccination, thus providing new insights into the immune response triggered against these viruses.
Assuntos
Anticorpos Neutralizantes , Anticorpos Antivirais , Surtos de Doenças , Imunidade Humoral , Vacina contra Febre Amarela , Febre Amarela , Vírus da Febre Amarela , Febre Amarela/imunologia , Febre Amarela/epidemiologia , Febre Amarela/virologia , Humanos , Brasil/epidemiologia , Vírus da Febre Amarela/imunologia , Vírus da Febre Amarela/genética , Anticorpos Neutralizantes/sangue , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/sangue , Anticorpos Antivirais/imunologia , Masculino , Vacina contra Febre Amarela/imunologia , Feminino , Adulto , Pessoa de Meia-Idade , Vacinação , Testes de Neutralização , Adulto Jovem , Idoso , AdolescenteRESUMO
BACKGROUND: The median age for Prostate Cancer (PCa) diagnosis is 66 years, but 10% are diagnosed before 55 years. Studies on early-onset PCa remain both limited and controversial. This investigation sought to identify and characterize germline variants within Brazilian PCa patients classified as either early or later onset disease. METHODS: Peripheral blood DNA from 71 PCa patients: 18 younger (≤ 55 years) and 53 older (≥ 60 years) was used for Targeted DNA sequencing of 20 genes linked to DNA damage response, transcriptional regulation, cell cycle, and epigenetic control. Subsequent genetic variant identification was performed and variant functional impacts were analyzed with in silico prediction. RESULTS: A higher frequency of variants in the BRCA2 and KMT2C genes across both age groups. KMT2C has been linked to the epigenetic dysregulation observed during disease progression in PCa. We present the first instance of KMT2C mutation within the blood of Brazilian PCa patients. Furthermore, out of the recognized variants within the KMT2C gene, 7 were designated as deleterious. Thirteen deleterious variants were exclusively detected in the younger group, while the older group exhibited 37 variants. Within these findings, 4 novel variants emerged, including 1 designated as pathogenic. CONCLUSIONS: Our findings contribute to a deeper understanding of the genetic factors associated with PCa susceptibility in different age groups, especially among the Brazilian population. This is the first investigation to explore germline variants specifically in younger Brazilian PCa patients, with high relevance given the genetic diversity of the population in Brazil. Additionally, our work presents evidence of functionally deleterious germline variants within the KMT2C gene among Brazilian PCa patients. The identification of novel and functionally significant variants in the KMT2C gene emphasizes its potential role in PCa development and warrants further investigation.