Correlato neurobiológico de los síntomas premotores del parkinson: el origen en la teoría de Braak / Neurobiological correlate of parkinson's premotor symptoms: the origin in Braak's theory / Correlação neurobiológica dos sintomas pré-motores de parkinson: a origem na teoria de Braak

El diagnóstico de enfermedad de Parkinson (ED) se basa en las principales manifestaciones motoras: bradicinesia en combinación con temblor en reposo, rigidez o ambos. Cuando se realiza el diagnóstico basado en la sintomatología motora clínica típica ya se han perdido hasta el 60 % de las neuronas dopaminérgicas de la sustancia negra pars compacta mesencefálica. La identificación de los síntomas premotores son un marcador temprano para sospechar la aparición futura de la enfermedad, así como su progresión y gravedad. La hipótesis sobre la patogénesis que mejor expone la progresión de la enfermedad es la teoría de Braak. Esta se basa en la aparición y presencia de cuerpos de Lewy en diferentes estructuras anatómicas, las cuales representadas en cada uno de sus seis estadios y podrían ser la explicación biológica de los síntomas premotores, motores y no motores. La detección temprana de los síntomas premotores puede tener repercusiones positivas en el enfoque, seguimiento, diagnóstico y tratamiento de la EP. El propósito de este artículo es identificar las aproximaciones neurológicas descritas por la teoría de Braak para los síntomas premotores de la enfermedad de Parkinson de acuerdo con la literatura publicada en los últimos 20 años.

The diagnosis of Parkinson's disease (PD) is based on the main motor manifestations: bradykinesia in combination with tremor at rest, rigidity, or both. When the diagnosis is made based on typical clinical motor symptoms, up to 60 % of the dopaminergic neurons of the mesencephalic substantia nigra pars compacta have already been lost. The identification of premotor symptoms is an early marker to suspect the future appearance of the disease, as well as its progression and severity. The hypothesis about the pathogenesis that best exposes the progression of the disease is Braak's theory. It is based on the appearance and presence of Lewy bodies in different anatomical structures, which are represented in each of its six stages and could be the biological explanation biological of premotor, motor, and non-motor symptoms. Early detection of premotor symptoms can have positive repercussions in the approach, follow-up, diagnosis and treatment of PD. The purpose of this article is to identify the neurological approaches described by Braak's theory for the premotor symptoms of Parkinson's disease according to the literature published in the last 20 years.

O diagnóstico da doença de Parkinson (DP) baseia-se nas principais manifestações motoras: bradicinesia combinada com tremor de repouso, rigidez ou ambos. Quando o diagnóstico é feito com base em sintomas clínicos motores típicos, até 60% dos neurônios dopaminérgicos da substância negra pars compacta mesencefálica já foram perdidos. A identificação de sintomas pré-motores é um marcador precoce para suspeitar do futuro aparecimento da doença, bem como da sua progressão e gravidade. A hipótese sobre a patogênese que melhor expõe a progressão da doença é a teoria de Braak. Isto se baseia no aparecimento e presença de corpos de Lewy em diferentes estruturas anatômicas, que estão representados em cada uma de suas seis etapas e podem ser a explicação biológica dos sintomas pré-motores, motores e não motores. A detecção precoce de sintomas pré-motores pode repercutir positivamente na abordagem, acompanhamento, diagnóstico e tratamento da DP. O objetivo deste artigo é identificar as abordagens neurológicas descritas pela teoria de Braak para os sintomas pré-motores da doença de Parkinson de acordo com a literatura publicada nos últimos 20 anos.

Hepatic and skeletal muscle tissue immunometabolism in trained rats / Inmunometabolismo del tejido hepático y muscular esquelético de ratas entrenadas / Imunometabolismo tecidual hepático e muscular esquelético de ratos treinados

ABSTRACT Introduction: Physical exercise can be an alternative for preventing and treating the harmful effects of obesity, mainly inflammatory effects on skeletal muscle and liver tissues. However, no consensus exists regarding this purpose's best physical training model. Objective: Evaluate morphological, metabolic, and inflammatory alterations in rats' skeletal and hepatic muscle tissues caused by aerobic and resistance training. Methods: 24 Wistar rats were divided into sedentary (S), aerobic (AE), and resistance training (R) groups. Blood glucose, total cholesterol, and serum triglycerides were measured periodically. After euthanasia, body mass was measured to calculate the total mass gain during the experiment. High-density lipoprotein (HDL) was measured. Adipose tissue was extracted to calculate its percentage relative to body mass and the liver, soleus, and gastrocnemius muscles for morphological analyses and concentrations of glycogen, lipids, and Tumor Necrosis Factor α (TNF-α). The Kruskall-Wallis test and Dunn's post-test were performed for statistical analysis, adopting p<0.05. Results: Both training models reduced the percentage of adipose tissue, body mass gain, and hepatic TNF-α concentration (p<0.05). AE increased serum HDL, gastrocnemius fiber diameter and reduced the fractal dimension in the soleus (p<0.05). R reduced blood glucose and serum and liver lipids, increased liver and soleus glycogen concentrations, increased gastrocnemius fiber diameter, and decreased TNF-α (p<0.05). Conclusion: Both training models reduced body mass, relative visceral adipose tissue, serum total cholesterol concentration, and liver inflammation. However, resistance training was more effective in promoting metabolic effects in the liver and skeletal muscle and reducing muscle inflammation in rats. Level of Evidence V; Expert Opinion.

RESUMEN Introducción: El ejercicio físico puede ser una alternativa para prevenir y tratar los efectos nocivos de la obesidad, principalmente los efectos inflamatorios sobre los tejidos del músculo esquelético y del hígado. Sin embargo, no existe consenso sobre cuál es el mejor modelo de entrenamiento físico para este fin. Objetivo: Evaluar las alteraciones morfológicas, metabólicas e inflamatorias del entrenamiento aeróbico y de resistencia en sobre los tejidos músculo esqueléticos y hepáticos de ratas. Métodos: 24 ratas Wistar se dividieron en grupos sedentarios (S), aeróbicos (AE) y de entrenamiento de resistencia (R). Se midieron periódicamente glucosa en sangre, colesterol total y triglicéridos. Después de la eutanasia, se midió la masa corporal para calcular la ganancia de masa total durante el experimento. Se midió la lipoproteína de alta densidad (HDL). Se extrajo tejido adiposo para calcular su porcentaje relativo a la masa corporal, así como hígado, músculos sóleo y gastrocnemio para análisis morfológicos y concentraciones de glucógeno, lípidos y Factor de Necrosis Tumoral α (TNF-α). Para el análisis estadístico fueron utilizados Kruskall-Wallis y el post-test de Dunn, adoptando p<0,05. Resultados: Ambos entrenamientos redujeron el porcentaje de tejido adiposo, masa corporal y la concentración de TNF-α hepático (p<0,05). AE aumentó el HDL sérico, el diámetro de la fibra del gastrocnemio y redujo la dimensión fractal en el sóleo (p<0,05). R redujo la glucosa en sangre y los lípidos séricos y hepáticos, aumentó las concentraciones de glucógeno hepático y sóleo, aumentó el diámetro de la fibra del gastrocnemio y disminuyó el TNF-α (p<0,05). Conclusión: Ambos modelos de entrenamiento redujeron la masa corporal, el tejido adiposo visceral relativo, la concentración sérica de colesterol total y la inflamación hepática. El entrenamiento de resistencia demostró ser más eficaz para promover los efectos metabólicos en el hígado y el músculo esquelético, además de reducir la inflamación muscular en ratas. Nivel de Evidencia V; Opinión del Especialista.

RESUMO Introdução: O exercício físico pode se apresentar como uma alternativa para prevenção e tratamento de efeitos deletérios da obesidade, principalmente efeitos inflamatórios sobre os tecidos muscular esquelético e hepático. No entanto, não há consenso quanto ao melhor modelo de treinamento físico para tal finalidade. Objetivos: Avaliar alterações morfológicas, metabólicas e inflamatórias dos treinamentos aeróbico e resistido sobre os tecidos muscular esquelético e hepático de ratos. Métodos: 24 ratos Wistar foram divididos nos grupos sedentário (S), treinamento aeróbico (AE) e resistido (R). Glicemia, colesterol total e triglicerídeos séricos foram mensurados periodicamente. Após a eutanásia, a massa corporal foi mensurada para calcular o ganho total de massa durante o experimento. A lipoproteína de alta densidade (HDL) foi dosada. O tecido adiposo foi extraído para cálculo de sua porcentagem relativa à massa corporal assim como o fígado e os músculos sóleo e gastrocnêmio para as análises morfológicas e das concentrações de glicogênio, lipídios e Fator de Necrose Tumoral α (TNF-α). Para análise estatística, foram utilizados o teste de Kruskall-Wallis e o pós-teste de Dunn, adotando-se p<0,05. Resultados: Ambos os modelos de treinamento reduziram o percentual de tecido adiposo, ganho de massa corporal e concentração hepática de TNF-α (p<0,05). AE aumentou o HDL sérico, o diâmetro das fibras do gastrocnêmio e reduziu a dimensão fractal no sóleo (p<0,05). R reduziu a glicemia e os lipídios séricos e hepáticos, aumentou a concentração de glicogênio hepático e sóleo, aumentou o diâmetro das fibras gastrocnêmicas e diminuiu o TNF-α (p<0,05). Conclusão: Ambos os modelos de treinamento reduziram a massa corporal, o tecido adiposo visceral relativo, a concentração sérica de colesterol total e a inflamação hepática. No entanto, o treinamento resistido mostrou-se mais eficaz em promover efeitos metabólicos no fígado e no músculo esquelético, além de reduzir a inflamação muscular em ratos. Nível de Evidência V; Opinião do Especialista.

Increased Circulating Fetuin-A Levels in Patients with Atrial Fibrillation

Abstract Background Biomarkers related to the pathogenesis of atrial fibrillation (AF) have attracted the attention of experts. One of these recently studied biomarkers is Fetuin-A. Objectives This study aimed to evaluate the relationship between serum Fetuin-A levels and AF. Methods This study used the convenience sampling method, based on inclusion criteria and consent to participate in the study. The Shapiro-Wilk test was used to confirm the normal distribution of all continuous variables. Categorical variables were presented using absolute and relative frequencies. Both groups (48 patients with AF and 47 controls) were compared in terms of biochemical, hematological, and echocardiographic findings and Fetuin-A. the Chi-square or Fisher's exact test were used to compare groups concerning categorical variables. Continuous variables were compared using the independent samples t-test. P<0.05 was considered statistically significant. Results Serum Fetuin-A values increased in AF patients when compared to the controls (544±49 μg/mL versus 484±46 μg/mL, p=0.001). Moreover, Fetuin-A level was independently associated with AF — AOR = 0.978, 95%; confidence interval (CI) 0.969-988, p < 0.001. The cut-off values in Fetuin-A levels in patients with AF were >511.80 μg/mL with a sensitivity of 75% and a specificity of 73% — area under the curve (AUC) = 0.804, 95% CI = 0.715 - 0.892. Conclusions According to this study, there was a relationship between serum Fetuin-A levels and AF, regardless of conventional cardiovascular risk factors. Therefore, Fetuin-A may play a role in the pathophysiology of AF. Prospectively designed cohort studies are necessary to assess whether or not the results can be generalized for other populations.

An appraisal to Hans Berger by the time of his 150th birthday: the human EEG and tales of blood flow, heat and brain waves / Um ensaio sobre o aniversário de 150 anos de Hans Berger: uma história de sangue, calor e ondas cerebrais

Abstract More than 100 years of research have passed by and still the human electroencephalogram (EEG) remains a puzzle to be solved. Starting from his studies on plethysmography until his theories on brain thermodynamics, Hans Berger was able to refine his method of recording cortical signs with the apparatus at his disposal in an ordinary neuropsychiatric yard towards an early account of human EEG. This review is an appraisal of his contribution to the field of modern neurophysiology.

Resumo Mais de 100 anos se passaram e o eletroencefalograma humano (EEG) continua sendo um enigma a ser desvendado. A partir de seus estudos sobre pletismografia até suas teorias sobre termodinâmica cerebral, Hans Berger conseguiu refinar seu método de registro da atividade elétrica cortical com os equipamentos a sua disposição em uma ala psiquiátrica comum produzindo uma descrição acurada do EEG humano. Esta revisão é um breve resumo de sua contribuição para o campo da neurofisiologia moderna.

Zarzio Ameliorates Non-alcoholic Fatty Liver Induced By a High Fat Diet in a Rat Experimental Model: A Histological and Immunohistochemical Study

SUMMARY: The therapeutic effect of a granulocyte-colony stimulating factor (G-CSF) biosimilar drug, zarzio, on non-alcoholic fatty liver disease (NAFLD) in a rat model was investigated in this study. Thirty-two rats were randomly divided into four groups. Groups I and II were fed a standard laboratory diet, whereas groups III and IV were fed a high fat diet (HFD) for 14 weeks. After 12 weeks of feeding, groups I and III were administered normal saline, and groups II and IV were intraperitoneally administered zarzio (200 mg/kg/day) for two consecutive weeks. Hematoxylin-eosin (H&E) staining was used to assess hepatic and pancreatic morphology in all groups, oil red O (ORO) staining for lipid accumulation, Masson's staining for fibrosis, and immunohistochemistry assay for hepatic protein expression of insulin receptor substrate 1 (IRS1), nuclear factor erythroid 2-related factor 2 (Nrf2), tumour necrosis factor alpha (TNF-α) and pancreatic caspase-3. The NAFLD rats (group III) developed hepatic steatosis with increased lipid accumulation, perisinusoidal fibrosis, upregulated IRS1, TNF-α (all P<0.05) without a significant increase in Nrf2 protein expression compared with normal control. In comparison, model rats treated with zarzio (group IV) showed significant rejuvenation of the hepatic architecture, reduction of fat accumulation, and fibrosis. This was accompanied by the upregulation of Nrf2, downregulation of IRS1 and TNF-α protein expression (all P<0.05). No correlation was detected between NAFLD and non-alcoholic fatty pancreas disease (NAFPD). However, the pancreatic β-cells in group III showed increased caspase-3 expression, which was decreased (P<0.05) in group IV. In conclusion, zarzio ameliorates NAFLD by improving the antioxidant capacity of liver cells, reducing hepatic IRS1, TNF-α protein expression and pancreatic β-cells apoptosis, suggesting that zarzio could be used as a potential therapy for NAFLD.

En este estudio se investigó el efecto terapéutico de un fármaco biosimilar del factor estimulante de colonias de granulocitos (G-CSF), zarzio, sobre la enfermedaddel hígado graso no alcohólico (NAFLD) en un modelo de rata. Treinta y dos ratas se dividieron aleatoriamente en cuatro grupos. Los grupos I y II fueron alimentados con una dieta estándar de laboratorio, mientras que los grupos III y IV fueron alimentados con una dieta alta en grasas (HFD) durante 14 semanas. Después de 12 semanas de alimentación, a los grupos I y III se les administró solución salina normal, y a los grupos II y IV se les administró zarzio por vía intraperitoneal (200 mg/kg/ día) durante dos semanas consecutivas. Se utilizó tinción de hematoxilina-eosina (H&E) para evaluar la morfología hepática y pancreática en todos los grupos, tinción con rojo aceite O (ORO) para la acumulación de lípidos, tinción de Masson para la fibrosis y ensayo de inmunohistoquímica para la expresión de la proteína hepática del sustrato 1 del receptor de insulina (IRS1), factor nuclear eritroide 2 relacionado con el factor 2 (Nrf2), factor de necrosis tumoral alfa (TNF-α) y caspasa-3 pancreática. Las ratas NAFLD (grupo III) desarrollaron esteatosis hepática con aumento de la acumulación de lípidos, fibrosis perisinusoidal, IRS1 y TNF-α regulados positivamente (todos P <0,05) sin un aumento significativo en la expresión de la proteína Nrf2 en comparación con el control normal. En comparación, las ratas modelo tratadas con zarzio (grupo IV) mostraron un rejuvenecimiento significativo de la arquitectura hepática, una reducción de la acumulación de grasa y fibrosis. Esto estuvo acompañado por la regulación positiva de Nrf2, la regulación negativa de la expresión de la proteína IRS1 y TNF-α (todas P <0,05). No se detectó correlación entre NAFLD y la enfermedad del páncreas graso no alcohólico (NAFPD). Sin embargo, las células β pancreáticas en el grupo III mostraron una mayor expresión de caspasa-3, que disminuyó (P <0,05) en el grupo IV. En conclusión, zarzio mejora la NAFLD al mejorar la capacidad antioxidante de las células hepáticas, reduciendo el IRS1 hepático, la expresión de la proteína TNF-α y la apoptosis de las células β pancreáticas, lo que sugiere que zarzio podría usarse como una terapia potencial para la NAFLD.

Hepatitis B and Celiac Disease: A Cause for Concern?

Some theories suggest that the development of the immune response to clear hepatitis B triggers the intestinal tissue damage seen in celiac disease in genetically predisposed individuals. Although the role of hepatitis B virus infection in the development of autoimmune diseases has been widely discussed in the literature, it remains a controversial topic. Our objective is to review whether there is an association between hepatitis B and celiac disease and the particularities of vaccination against hepatitis B in celiac patients.

Algunas teorías sugieren que el desarrollo de la respuesta inmunitaria para la eliminación de la hepatitis B desencadena el daño del tejido intestinal observado en la enfermedad celíaca en individuos genéticamente predispuestos. Aunque el papel de la infección por el virus de la hepatitis B en el desarrollo de enfermedades autoinmunes se ha discutido ampliamente en la literatura, sigue siendo un tema controvertido. Nuestro objetivo es revisar si existe una asociación entre la hepatitis B y la enfermedad celíaca y las particularidades de la vacunación contra la hepatitis B en pacientes celíacos.

Aspectos clínicos, laboratoriais e evolutivos de pacientes pediátricos com doença hepática por deficiência de alfa 1-antitripsina / Clinical, laboratorial and evolutionary aspects of pediatric patients with liver disease due to alpha 1-antitrypsin deficiency

ABSTRACT Background: Alpha 1-antitrypsin deficiency (AATD) is a hereditary codominant autosomal disease. This liver disease ranges from asymptomatic cases to terminal illness, which makes early recognition and diagnosis challenging. It is the main cause of pediatric liver transplantation after biliary atresia. Objective: To describe the clinical characteristics, as well as those of histologic and laboratory tests, phenotypic and/or genetic evaluation and evolution of a cohort of pediatric patients with AATD. Methods: This is a retrospective observational study of 39 patients with confirmed or probable AATD (without phenotyping or genotyping, but with suggestive clinical features, low serum alpha 1-antitrypsin (AAT) level and liver biopsy with PAS granules, resistant diastasis). Clinical, laboratory and histological varia­bles, presence of portal hypertension (PH) and survival with native liver have been analyzed. Results: A total of 66.7% of 39 patients were male (26/39). The initial manifestation was cholestatic jaundice in 79.5% (31/39). Liver transplantation was performed in 28.2% (11/39) of patients. Diagnosis occurred at an average of 3.1 years old and liver transplantation at 4.1 years of age. 89.2% (25/28) of the patients with confirmed AATD were PI*ZZ or ZZ. The average AAT value on admission for PI*ZZ or ZZ patients was 41.6 mg/dL. All transplanted patients with phenotyping or genotyping were PI*ZZ (or ZZ). Those who were jaundiced on admission were earlier referred to the specialized service and had higher levels of GGT and platelets on admission. There was no significant difference in the survival curve when comparing cholestatic jaundiced to non-cholestatic jaundiced patients on admission. Comparing patients who did or did not progress to PH, higher levels of AST and APRI score at diagnosis (P=0.011 and P=0.026, respectively) were observed and in the survival curves patients with PH showed impairment, with 20.2% survival with native liver in 15 years. Conclusion: Jaundice is an important clinical sign that motivates referral to a specialist, but it does not seem to compromise survival with native liver. Patients progressing to PH had higher AST, APRi score on admission and significantly impaired survival with native liver. It is important to pay attention to these signs in the follow-up of patients with AATD.

RESUMO Contexto: Deficiência de alfa 1-antitripsina (DAAT) é uma doença hereditária, de caráter autossômico codominante. A apresentação da doença hepática varia desde casos assintomáticos até doença terminal, o que dificulta reconhecimento e diagnóstico precoces. É a principal causa de transplante hepático pediátrico após atresia de vias biliares. Objetivo: Descrever as características clínicas, de exames laboratoriais, histológicos, avaliação fenotípica e/ou genética e sobrevida de uma coorte de pacientes pediátricos com DAAT. Métodos: Estudo observacional retrospectivo de 39 pacientes com diagnóstico de DAAT confirmada ou provável (sem fenotipagem ou genotipagem, mas com clínica sugestiva, baixo nível sérico de alfa 1-antitripsina (A1AT) e biópsia hepática com grânulos PAS, diástase resistentes). Variáveis clínicas, laboratoriais, histológicas, presença de hipertensão portal (HP) e sobrevida com fígado nativo foram analisadas. Resultados: Dos 39 pacientes, 66,7% eram do sexo masculino (26/39). A manifestação inicial foi icterícia colestática em 79,5% (31/39). Em 28,2% (11/39) houve necessidade de transplante hepático. O diagnóstico ocorreu com uma idade média de 3,1 anos e, o transplante hepático, 4,1 anos. Dos pacientes com DAAT confirmada, 89,2% (25/28) eram PI*ZZ ou ZZ. O valor médio de A1AT na admissão de pacientes PI*ZZ ou ZZ foi 41,6 mg/dL. Todos os transplantados com fenotipagem ou genotipagem eram PI*ZZ (ou ZZ). Os ictéricos à admissão foram referenciados mais cedo ao serviço especializado e apresentaram níveis mais elevados de GGT e plaquetas à admissão. Não houve diferença significativa na curva de sobrevida ao compararmos icterícia colestática ou não à admissão. Ao comparar os pacientes que progrediram ou não para HP, observou-se níveis mais elevados de AST e APRI escore ao diagnóstico (P=0,011 e P=0,026, respectivamente) e, nas curvas de sobrevida, pacientes com HP apresentaram comprometimento, com 20,2% de sobrevida com fígado nativo em 15 anos. Conclusão: Icterícia é um sinal clínico importante que motiva o encaminhamento ao especialista, mas parece não comprometer a sobrevida com fígado nativo. Pacientes com evolução para HP tiveram AST e escore APRi mais elevados à admissão e comprometimento significativo da sobrevida com fígado nativo. Importante atentar a esses sinais no seguimento de pacientes com DAAT.

Respuesta de procalcitonina ante co-infección e infección secundaria por bacterias multirresistentes en pacientes COVID -19 / Procalcitonin response in co-infection and secondary infection by multidrug resistant bacteria in COVID -19 patients

INTRODUCCIÓN. La procalcitonina, es un biomarcador que puede usarse como apoyo diagnóstico en infecciones bacterianas y la monitorización del tratamiento antibiótico, sobre todo en pacientes con sepsis. De ahí que, fue utilizado durante la pandemia COVID-19 OBJETIVO. Determinar los valores de procalcitonina en pacientes con COVID-19 y definir una p osible correlación entre su incremento y vinculación en coinfección o infección secundaria por Klebsiella pneumoniae y Pseudomonas aeruginosa con multidrogo resistencia y resistencia extendida a los antibióticos. MATERIALES Y MÉTODOS. Estudio retrospectivo observacional, descriptivo transversal, realizado del 1 de mayo al 31 de octubre del 2020 en el Hospital de Especialidades Carlos Andrade Marín sobre 7028 pacientes adultos, hospitalizados, con diagnóstico de COVID-19, y resultados de procalcitonina, cuyas muestras de secreción traqueal y/o hemocultivo presentaron desarrollo de Klebsiella pneumoniae y Pseudomonas aeruginosa. Su análisis estadístico fue desarrollado mediante la prueba Chi Cuadrado de Pearson. RESULTADOS. Se recibieron 861 muestras de hemocultivo y 391 de secreción traqueal, obteniéndose: 32% aislamientos de Klebsiella pneumoniae y Pseudomonas aeruginosa multidrogo y extremadamente resistente. Entre los pacientes COVID-19 que fallecieron, 34,4% mostraron incrementos de procalcitonina. Al contrario, entre los pacientes que sobrevivieron sólo en 8,8% se observó incrementos de procalcitonina evidenciándose un vínculo entre el incremento de procalcitonina y mortalidad. CONCLUSIONES. No existe diferencia en relación al incremento en los valores de procalcitonina en pacientes COVID-19 con co-infección o infección secundaria por Klebsiella pneumoniae y Pseudomonas aeruginosa multidrogo y extremadamente resistente y los valores de procalcitonina en pacientes con coinfección e infección secundaria con otro tipo de aislamientos bacterianos.

INTRODUCTION. Procalcitonin is a biomarker that can be used as a diagnostic support in bacterial infections and the monitoring of antibiotic treatment, especially in patients with sepsis. Hence, it was used during the COVID-19 pandemic OBJECTIVE. To determine the values of procalcitonin in patients with COVID-19 and to define a possible correlation between its increase and linkage in co-infection or secondary infection by Klebsiella pneumoniae and Pseudomonas aeruginosa with multidrug resistance and extended resistance to antibiotics. MATERIALS AND METHODS. Retrospective observational, descriptive cross-sectional study, conducted from May 1 to October 31, 2020 at the Hospital de Especialidades Carlos Andrade Marín on 7028 adult patients, hospitalized, with diagnosis of COVID-19, and procalcitonin results, whose tracheal secretion and/or blood culture samples presented development of Klebsiella pneumoniae and Pseudomonas aeruginosa. Their statistical analysis was developed using Pearson's Chi-squared test. RESULTS. We received 861 blood culture and 391 tracheal secretion samples, obtaining: 32% isolates of Klebsiella pneumoniae and multidrug-resistant and extremely resistant Pseudomonas aeruginosa. Among the COVID-19 patients who died, 34.4% showed increased procalcitonin levels. On the contrary, among patients who survived, only 8.8% showed increased procalcitonin levels, showing a link between increased procalcitonin levels and mortality. CONCLUSIONS. There is no difference in relation to the increase in procalcitonin values in COVID-19 patients with co-infection or secondary infection by Klebsiella pneumoniae and multidrug-resistant and extremely resistant Pseudomonas aeruginosa and procalcitonin values in patients with co-infection and secondary infection with other types of bacterial isolates.

Tratamiento de la enfermedad de Pompe / Treatment of Pompe Disease

Introducción: La enfermedad de Pompe es un trastorno de origen genético causado por la deficiencia de la enzima alfa-glucosidasa ácida, que se caracteriza por el acumulo anormal de glucógeno en los músculos y otros tejidos, generando una debilidad muscular progresiva, la cual debe ser diagnosticada y tratada de forma oportuna, ya que de esto dependerá el pronóstico, la sobrevida y la funcionalidad de los pacientes con esta condición. Contenidos: El abordaje multidisciplinario incluye tanto una adecuada valoración y soporte nutricional como el inicio del tratamiento modificador de enfermedad a través de la terapia de reemplazo enzimático, que a su vez dependerá de la forma de presentación, la variante genética, el perfil inicial del paciente, las condiciones especiales que puedan existir y las metas propias para cada paciente. Para garantizar un manejo adecuado, se deben realizar estudios de seguimiento con parámetros objetivos, evaluar posibles eventos secundarios e instaurar su manejo en caso de presentarlos. Conclusiones: El pronóstico de esta enfermedad dependerá del inicio oportuno del tratamiento, la implementación de pautas nutricionales adecuadas y el establecimiento del seguimiento de los parámetros clínicos y paraclínicos para cada uno de los pacientes.

Introduction: Pompe disease is a disorder of genetic origin caused by the deficiency of the acid alpha-glucosidase enzyme, which is characterized by the abnormal accumulation of glycogen in the muscles and other tissues, generating progressive muscle weakness, which must be diagnosed and treated in a timely manner, since the prognosis, survival, and functionality of patients with this condition will depend on this. Contents: The multidisciplinary approach includes both an adequate evaluation and nutritional support as well as the initiation of disease-modifying treatment through enzyme replacement therapy, which in turn will depend on the form of presentation, the genetic variant, the initial profile of the patient, the special conditions that may exist and the specific goals for each patient. To guarantee adequate management, follow-up studies must be carried out with objective parameters, evaluate possible secondary events and establish their management in case of presenting them. Conclusions: The prognosis of this disease will depend on the timely initiation of treatment, the implementation of adequate nutritional guidelines and the establishment of monitoring of clinical and paraclinical parameters for each of the patients.

Sonhos possíveis e a relação transferencial / Possible dreams and the transferential relationship / Les rêves possibles et la relation transférentielle

Ogden (2010a) apresenta-nos uma teoria da clínica em que o sonhar é tomado como função de elaboração inconsciente, sendo a incapacidade do sujeito de "sonhar sua experiência emocional" um indicador de sofrimento psíquico. Tendo essa ideia como referência, assim como a teorização de Bion sobre a função alfa e o pensamento-sonho, falaremos no presente trabalho sobre o comprometimento da capacidade de sonhar e seus ecos para o psiquismo do sujeito. Com a apresentação de um caso clínico traremos ainda uma discussão sobre o mecanismo da identificação projetiva e seu valor de comunicação em análise.

Ogden (2010a) presents us with a theory of the clinic in which dreaming is taken as a function of unconscious elaboration, being the subject's inability to "dream his emotional experience" an indicator of psychological suffering. Taking this idea as a reference, as well as Bion's theorization about the alpha function and dream thoughts, in this work we will approach the compromise of the ability to dream and its echoes to the subject's psyche. We will present a clinical case and we will also discuss the mechanism of projective identification and its value of communication in analytical treatment.

Ogden (2010a) nous présente une théorie de la clinique dans laquelle le rêve est pris en fonction de l'élaboration inconsciente, et l'incapacité du sujet à «rêver son expérience émotionnelle¼ étant un indicateur de la souffrance psychique. Prenant cette idée comme référence, ainsi que la théorisation de Bion sur la fonction alpha et la pensée du rêve, nous parlerons dans le présent travail de l'incapacité de rêver et de ses échos à la psyché du sujet. Avec la présentation d'un cas clinique, nous aborderons également le mécanisme d'identification projective et sa valeur de communication en cours d'analyse.

Evaluation of IL-4, MIP-1α, and MMP-9 gene expression levels in peri-implant tissues in peri-implantitis

Abstract This case-control study evaluated the gene expression levels of interleukin (IL)-4, macrophage inflammatory protein type 1 alpha (MIP-1α), and metalloproteinase (MMP)-9, factors involved in the formation of giant cells in healthy peri-implant tissue and peri-implantitis. Thirty-five subjects (15 healthy and 20 with peri-implantitis), who met the inclusion and exclusion criteria, were included in this study. The peri-implant tissue biopsies were subjected to total RNA extraction, DNAse treatment, and cDNA synthesis. Subsequently, the reaction of real-time PCR was performed to evaluate the gene expression levels of IL-4, MIP-1α, and MMP-9 concerning the reference gene. IL-4 gene expression showed higher (18-fold) values in the Peri-Implantitis Group of Patients when compared with the Healthy (Control) Group (p<0.0001). Although MIP- 1α and MMP-9 gene expression levels were higher in diseased implants, they showed no significant differences (p=0.06 and p=0.2337), respectively. Within the limitations of this study, the results showed that in tissues affected by peri-implantitis, only levels of Il-4 were increased when compared with tissues in the control group.

Resumo Este estudo caso-controle teve como objetivo avaliar a expressão gênica dos níveis de interleucina (IL)-4, proteína inflamatória de macrófagos tipo alfa 1 (MIP-1α) e metalopreoteinase (MMP)-9, todos fatores envolvidos na formação de células gigantes em tecidos peri-implantares saudáveis e com peri-implantite. Trinta e cinco indivíduos (15 saudáveis e 20 com peri-implantite) foram incluídos nesse estudo seguindo os critérios de inclusão e exclusão. Os tecidos peri-implantares foram submetidos a extração do RNA total, tratamento de DNAse e síntese de cDNA. Subsequentemente, a reação de PCR em tempo real foi realizada para avaliar os níveis da expressão de IL-4, MIP-1α, e MMP-9 em relação ao gene de referência. O nível de expressão de IL-4 foi estatisticamwente maior (18 vezes) nos tecidos de pacientes com peri-implantite quando comparados aos pacientes saudáveis (grupo controle) (p<0,0001). Embora os níveis de expressão de MIP- 1α e MMP-9 apresentassem maiores valores nos implantes doentes, esses níveis não foram estatisticamente significantes (p=0.06 and p=0.2337) respectivamente. Dentro das limitações desse estudo, os resultados mostraram que nos tecidos afetados pela peri-implantite, apenas os nívies de IL-4 estavam aumentados quando comparados ao grupo controle.

Anaphylaxis and systemic mastocytosis caused by Solenopsis invicta stings / Anafilaxia e mastocitose sistêmica ocasionada pela Solenopsis invicta

Indolent systemic mastocytosis is a rare disease characterized by an increased number of mast cells in the bone marrow and other tissues, such as the liver, spleen, lymph nodes, and skin. Patients with indolent systemic mastocytosis and high serum tryptase levels are at risk for Hymenoptera venom-induced anaphylaxis. Hymenoptera venom immunotherapy in patients with specific IgE is safe and effective. While some patients can receive ultra-rush venom immunotherapy with minimal side effects, omalizumab effectively protects against anaphylaxis during the build-up phase.

A mastocitose sistêmica indolente é uma doença rara caracterizada por um número aumentado de mastócitos na medula óssea e em outros tecidos, como fígado, baço, linfonodos e pele. Pacientes com mastocitose sistêmica indolente e altos níveis séricos de triptase correm risco de anafilaxia induzida pelo veneno dos Hymenoptera. A imunoterapia com veneno de himenópteros em pacientes com IgE específica é segura e eficaz. Embora alguns pacientes possam receber imunoterapia com veneno ultrarrápido com efeitos colaterais mínimos, o omalizumabe protegeu efetivamente contra a anafilaxia durante a fase de acúmulo.

Masquerade syndrome in ocular surface squamous neoplasia / Síndrome mascarada em neoplasia escamosa da superfície ocular

ABSTRACT The aim of this study was to alert the ophthalmic community to an atypical manifestation of ocular surface squamous neoplasia, which may delay diagnosis and treatment and result in a guarded visual prognosis and significant sequelae. A 61-year-old immunocompetent man presented with an initial diagnosis of necrotizing scleritis in the right eye for 3 months. He was treated with systemic prednisone but experienced persistent pain and low visual acuity. Conjunctival biopsy of the affected region confirmed the diagnosis of invasive ocular surface squamous neoplasia, which progressed with intraocular and orbital invasion; thus, exenteration was performed. Masquerade syndrome should be suspected in patients with nodulo-ulcerative lesions of the conjunctiva and sclera. This clinical can be more aggressive, with a greater likelihood of intraocular and orbital involvement. The earlier the diagnosis and treatment, the better the patient prognosis.

RESUMO O objetivo é alertar a comunidade oftalmológica sobre uma manifestação atípica de neoplasia escamosa da superfície ocular (OSSN) que pode levar a um atraso no diagnóstico e tratamento, evoluindo com prognóstico reservado e significativas sequelas. Homem, imunocompetente, 61 anos com diagnóstico inicial de esclerite necrosante em olho direito há 3 meses, em tratamento com prednisona sistêmica porém com persistência da dor e baixa acuidade visual. Realizado biópsia conjuntival em região acometida e diagnosticado como neoplasia escamosa da superfície ocular invasiva. Evolui com invasão intraocular e orbital sendo submetido a exenteração. Assim sendo, deve-se suspeitar de síndrome mascarada frente a um paciente com lesões nódulo-ulcerativas da conjuntiva e esclera. Essa forma clínica pode ser mais agressiva, com maior chance de comprometimento intraocular e orbital. Quanto mais precoces o diagnóstico e o tratamento, melhor o prognóstico para o paciente.

Comparative Analysis of TNF-alpha, TNF-R1, and TNF-R2 in Patients with Low-impact Fractures Due to Osteoporosis / Análise comparativa de TNF-alfa, TNF-R1 e TNF-R2 em pacientes com fraturas de baixo impacto decorrentes de osteoporose

Abstract Objective To analyze the serum levels of TNF-alpha and its TNF-R1 and TNF-R2 receptors in the blood of patients with low-impact fractures due to osteoporosis, comparing between genders and with healthy patients. Methods The present study was conducted with a blood sample of 62 patients, divided into patients with osteoporosis and healthy patients. The results were obtained using the ELISA method. Cytokine concentrations were determined based on the absorbance values obtained. Results Serum TNF-alpha levels were undetectable in female patients, while in males they were found only in one patient, with no significant difference. Similar results were found in the analyses of TNF-R1 and TNF-R2 levels, a significant increase in levels of TNF-alpha receptors in the groups of patients with osteoporosis compared with the control groupinbothsexes.There wasnosignificant difference between the sexes in the dosage of both receptors within the group with osteoporosis. There was also a positive and significant correlation in the levels of TNF-R1 and TNF-R2 only in women. Conclusion The significant increase in TNF-R1 and TNF-R2 levels in women with osteoporosis suggest that the release and expression of these receptors may be contributing differently to the development of osteoporosis in men and women.

Resumo Objetivo Analisar os níveis séricos de TNF-alfa e de seus receptores TNF-R1 e TNF-R2 no sangue de pacientes com fraturas de baixo impacto, decorrentes de osteoporose, comparando entre os sexos e com pacientes saudáveis. Métodos Oestudofoi realizadocom amostradesanguede 62 pacientes,divididos em pacientes com osteoporose e pacientes saudáveis. Os resultados foram obtidos através do método de ELISA. As concentrações de citocinas foram determinadas com base nos valores de absorbância obtidos. Resultados Os níveis séricos de TNF-alfa foram indetectáveis nos pacientes do sexo feminino, enquanto no masculino encontrou-se somente em um paciente, não havendo diferença significativa. Encontrou-se resultados semelhantes nas análises dos níveis de TNF-R1 e TNF-R2, aumento significativo nos níveis dos receptores de TNF-alfa nos grupos de pacientes com osteoporose em comparação com o grupo controle, em ambos os sexos. Não houve diferença significativa entre os sexos na dosagem de ambos os receptores dentro do grupo com osteoporose. Houve ainda correlação positiva e significativa nos níveis de TNF-R1 e TNF-R2 apenas nas mulheres. Conclusão O aumento significativo nos níveis de TNF-R1 e TNF-R2 em mulheres com osteoporose sugerem que a liberação e expressão destes receptores pode estar contribuindo de maneira distinta no desenvolvimento da osteoporose em homens e mulheres.

Quercetin and resveratrol are associated with the downregulation of TNFalpha/NF-kB/inos axis-mediated acute liver injury in rats induced by paracetamol poisoning / La quercetina y el resveratrol están asociados con la regulación decreciente de la lesión hepática aguda mediada por el eje TNF-alfa/NF-kB/inos en ratas inducida por envenenamiento con paracetamol

SUMMARY: Paracetamol (known as acetaminophen, or APAP) poisoning causes acute liver damage that can lead to organ failure and death. We sought to determine that APAP overdose can augment tumor necrosis factor-alpha (TNF-α)/ nuclear factor kappa B (NF-kB)/induced nitic oxide synthase (iNOS) axis-mediated hepatotoxicity in rats, and the anti-inflammatory polyphenolic compounds, quercetin (QUR) plus resveratrol (RES) can ameliorate these parameters. Therefore, we induced acute hepatotoxicity in rats using APAP overdose (2 g/kg, orally) and the protective group of rats were treated with 50 mg/kg QUR plus 30 mg/kg RES for one week before APAP ingestion. Animals were killed at day 8. APAP poisoning caused the induction of hepatic tissue levels of TNF-α, NF-kB, and iNOS, which were significantly (p<0.05) decreased by QUR+RES. QUR+RES, also inhibited liver injury biomarkers, alanine aminotransferase (ALT) and aspartate aminotransferase (AST). Additionally, a link between liver injury and TNF-α /NF-kB / iNOS axis mediated hepatotoxicity was observed. Thus, the presented data backing the conclusion that intoxication by paracetamol increases TNF-α / NF-kB / iNOS axis -mediated hepatotoxicity, and is protected by a combination of quercetin and resveratrol.

El envenenamiento por paracetamol (conocido como acetaminofeno o APAP) causa daño hepático agudo que puede provocar una insuficiencia orgánica y la muerte. El objetivo de este trabajo fue determinar si la sobredosis de APAP puede aumentar la hepatotoxicidad mediada por el eje del factor de necrosis tumoral alfa (TNF-α)/factor nuclear kappa B (NF-kB)/óxido nítico sintasa inducida (iNOS) en ratas, y si el polifenólico antiinflamatorio compuesto por quercetina (QUR) más resveratrol (RES) pueden mejorar estos parámetros. Por lo tanto, inducimos hepatotoxicidad aguda en ratas usando una sobredosis de APAP (2 g/kg, por vía oral). El grupo protector de ratas se trató con 50 mg/ kg de QUR más 30 mg/kg de RES durante una semana antes de la ingestión de APAP. Los animales se sacrificaron el día 8. El envenenamiento con APAP en el tejido hepático provocó la inducción de niveles de TNF-α, NF-kB e iNOS, que se redujeron significativamente (p<0,05) con QUR+RES. QUR+RES, también inhibió los biomarcadores de daño hepático, la alanina aminotransferasa (ALT) y el aspartato aminotransferasa (AST). Además, se observó una relación entre la lesión hepática y la hepatotoxicidad mediada por el eje TNF-α /NF-kB/iNOS. Por lo tanto, los datos presentados respaldan la conclusión de que la intoxicación por paracetamol aumenta la hepatotoxicidad mediada por el eje TNF-α /NF-kB / iNOS, y está protegida por una combinación de quercetina y resveratrol.

The effect of Vitamin E supplementation on inflammatory biomarkers and oxidative stress in patients with chronic kidney disease on hemodialysis: A systematic review

Hemodialysis, along with chronic kidney disease (CKD), intensifies the inflammatory process and oxidative stress in patients undergoing treatment. In this context, Vitamin E supplementation can mitigate the deleterious effects resulting from these processes. This is a systematic review whose objective was to evaluate the effect of Vitamin E supplementation on inflammatory biomarkers and oxidative stress in patients with CKD on hemodialysis. This review was prepared according to the methodology for systematic reviews and meta-analyses (PRISMA) and the search was performed in Pubmed, Cochrane Library, Scopus and Web of Science databases. The risk of bias of the included studies was assessed with the Cochrane Risk of Bias Tool. Twelve studies developed between 2006 and 2020 were included in this review. Most of them (n= 11) used vitamin E doses ranging from 400 IU to 888 IU and the supplementation time ranged from 2 weeks to 12 months. Of all the 12 articles included, 25% (n= 3) analyzed supplementation on biomarkers of oxidative stress and 25% (n= 3) addressed these parameters simultaneously. A positive effect was observed in 58.4% of the studies (n= 7). Thus, Vitamin E supplementation can be effective in mitigating the inflammatory process and oxidative stress, however, it is worth noting that the effect depends on the dose and time of supplementation.

La hemodiálisis, junto con la enfermedad renal crónica (ERC), intensifica el proceso inflamatorio y el estrés oxidativo en los pacientes en tratamiento. En este contexto, la suplementación con vitamina E puede mitigar los efectos nocivos resultantes de estos procesos. Esta es una revisión sistemática cuyo objetivo fue evaluar el efecto de la suplementación con vitamina E sobre biomarcadores inflamatorios y estrés oxidativo en pacientes con ERC en hemodiálisis. La revisión se elaboró según la metodología para revisiones sistemáticas y metanálisis (PRISMA) y la búsqueda se realizó en las bases de datos Pubmed, Cochrane Library, Scopus y Web of Science. El riesgo de sesgo de los estudios incluidos se evaluó con la Herramienta Cochrane de Riesgo de Sesgo (Cochrane Risk of Bias Tool). En esta revisión se incluyeron doce estudios desarrollados entre 2006 y 2020. La mayoría (n= 11) utilizó dosis de vitamina E que oscilaban entre 400 UI y 888 UI y el tiempo de suplementación osciló entre 2 semanas y 12 meses. De los 12 artículos incluidos, 25% (n= 3) analizaba la suplementación en biomarcadores inflamatorios, 50% (n= 6) en biomarcadores de estrés oxidativo y 25% (n= 3) en estos parámetros simultáneamente. Se observó un efecto positivo en 58,4% de los estudios (n= 7). Por lo tanto, la suplementación con vitamina E puede ser efectiva para mitigar el proceso inflamatorio y el estrés oxidativo, sin embargo, vale la pena señalar que el efecto depende de la dosis y el tiempo de suplementación.

Oral lichen planus in a young patient: a case report with nine-year follow-up / Líquen plano oral em paciente jovem: um relato de caso com acompanhamento de nove anos

INTRODUCTION: Oral lichen planus is an inflammatory condition that affects the stratified squamous epithelium of the oral mucosa. It occurs more frequently in female patients and it is rarely observed in children, adolescents, or young adults. This study aims to report a case of oral lichen planus in a young patient with a nine-year followup. CASE REPORT: A 19-year-old man reported to the Dentistry Department with a complaint of an asymptomatic white lesion on the dorsum and left lateral border of his tongue, which had appeared a few weeks before. Two weeks later, a second lesion, very similar to the previous one, appeared on the central region of his tongue. An incisional biopsy was performed. The histological slides were stained with hematoxylin-eosin and the expression of interleukin-1beta (IL-1ß) and tumor necrosis factor-alpha (TNF-α) was assessed by immunohistochemistry. No pharmacological treatment was prescribed. The clinical and histopathological findings were suggestive of oral lichen planus. The IL-1ß/TNF-α expression was low. There was a spontaneous regression of the lesions after approximately one year. The nine-year follow-up showed no signs of recurrence. CONCLUSION: This case presents atypical features such as the age of the patient and the spontaneous remission of the lesions.

INTRODUÇÃO: O líquen plano oral é uma condição inflamatória que acomete o epitélio escamoso estratificado da mucosa oral. Ocorre mais frequentemente em pacientes do gênero feminino e é raramente encontrado em pacientes pediátricos ou juvenis. O objetivo do presente estudo é relatar um caso de líquen plano oral em um paciente jovem com acompanhamento de nove anos. RELATO DE CASO: Um rapaz de 19 anos procurou atendimento no Departamento de Odontologia com a queixa de uma lesão branca assintomática em região de dorso e borda lateral esquerda de sua língua, com tempo de evolução de algumas semanas. Duas semanas depois, uma segunda lesão, muito similar à primeira, apareceu na região central de sua língua. Uma biópsia incisional foi realizada. As lâminas histológicas foram coradas com hematoxilina-eosina e a expressão de interleucina-1beta (IL-1ß) e de fator de necrose tumoral alfa (TNF-α) foram avaliadas por imunohistoquímica. Nenhum tratamento farmacológico foi prescrito. Os achados clínicos e histopatológicos foram sugestivos de líquen plano oral. A expressão de IL-1ß/TNF-α foi baixa. Houve uma regressão espontânea das lesões após aproximadamente um ano. O acompanhamento de nove anos não detectou sinais de recorrência. CONCLUSÃO: Esse caso apresenta características atípicas, como a idade do paciente e a remissão espontânea das lesões.

Atrofia multisistémica del tipo cerebelosa: implicaciones patológicas de la conectividad neuronal / Multiple system atrophy cerebellar variant: pathological implica-tions of the neural connectivity

Introducción. La atrofia multisistémica (MSA) es una enfermedad neurodegenerativa progresiva que afecta principal-mente la materia blanca (WM, por su sigla en inglés). Este tipo de atrofia se caracteriza por ocasionar inclusiones cito-plasmáticas gliales de la proteína alfa-sinucleína, además de disminuir la integridad, la desmielinización y los cambios en los diámetros axonales de la WM (trastornos del movimiento). Objetivo. Evaluar los hallazgos patológicos de la conectividad encontrados en casos de atrofia multisistémica de tipo cerebelosa (MSA-C) y las posibles conexiones que estos muestran con las señales clínicas, la fisiopatología de la enferme-dad, la imagenología y los blancos terapéuticos mediante una revisión sistemática de la literatura científica disponible. Métodos. Se realizó una búsqueda bibliográfica en las bases de datos PubMed, ResearchGate, Embase y Scopus con los siguientes términos claves: "Multiple system atrophy" AND "therapy" OR "diagnostic imagining" OR "physiopa-thology" OR epidemiology". Se seleccionaron artículos, en español e inglés, publicados entre 1989 y 2022. Tras aplicar los criterios de inclusión y exclusión y eliminar duplicados, se seleccionaron 61 estudios que comparaban los temas objetivo del estudio. Resultados. La conectividad funcional disminuida en la red de control ejecutivo izquierdo (ECN), relacionada con los circuitos de los ganglios basales y el tálamo, ocasiona desconexión cerebelo-prefrontal y cerebelo-amigdaloide / parahipocampal, lo cual tiene manifestaciones neuro histopatológicas que están correlacionadas con ciertos hallazgos imagenológicos. Conclusión. Se evidenció que resultados de diversos estudios han permitido dar viabilidad a la comprensión de la co-nectividad nodal identificada y sus manifestaciones anatomo-patológicas y funcionales en el curso natural de la MSA-C.

Introduction. Multiple system atrophy (MSA) is a progressive neurodegenerative disease primarily affecting white mat-ter (WM). This type of atrophy is characterized by causing glial cytoplasmic inclusions of the alpha-synuclein protein and decreasing the integrity, demyelination, and changes in the axonal diameter (movement disorders). Objective. To evaluate the pathological findings of connectivity found in cases of Multiple system atrophy-cerebellar subtype (MSA-C) and the possible connections that these show with clinical signs, the pathophysiology of the disease, imaging and therapeutic targets through a systematic review of the available scientific literature. Methods. A bibliographic search was carried out in the PubMed, ResearchGate, Embase, and Scopus databases with the following key terms: "Multiple system atrophy" AND "therapy" OR "diagnostic imagining" OR "physiopathology" OR "epidemiology." Articles were selected in Spanish and English and published between 1989 and 2022. After apply-ing the inclusion and exclusion criteria and eliminating duplicates, 61 studies were selected that compared the study's target topics. Results. Decreased functional connectivity in the left executive control network (ECN), related to the circuits of the basal ganglia and thalamus, causes cerebellar-prefrontal and cerebellar-amygdaloid/parahippocampal disconnection, which has neuro histopathological manifestations that are correlated with specific imaging findings. Conclusion. It was evident that the results of various studies have made it possible to give viability to the understanding of the identified nodal connectivity and its anatomical-pathological and functional manifestations in the natural course of MSA-C.

Predictive factors for functional cure after sequential therapy with nucleos(t)ide analogues and pegylated interferon alfa-2b in treatment of chronic hepatitis B / 临床肝胆病杂志

Objective To investigate the independent predictive factors for functional cure after long-term nucleos(t)ide analogue (NUC) antiviral therapy followed by pegylated interferon α-2b therapy in chronic hepatitis B (CHB) patients. Methods A total of 162 CHB patients who were admitted to several hospitals in Qingdao, China, from 2018 to 2021 were enrolled as subjects, and all patients received pegylated interferon α-2b for at least 48 weeks after NUC therapy for one year or longer. According to whether HBsAg clearance was achieved at week 48 of pegylated interferon α-2b treatment, the patients were divided into functional cure group with 79 patients and non-cure group with 83 patients, and related clinical indices were compared between the two groups. The two-independent-samples t test and the Mann-Whitney U rank sum test were used for comparison of continuous data between two groups, and the chi-square test was used for comparison of categorical data between two groups. The Spearman correlation analysis was performed, and the univariate and multivariate logistic regression analyses were used to investigate the independent predictive factors for functional cure. The receiver operating characteristic (ROC) curve was plotted for related variables, and the area under the ROC curve (AUC) was used to evaluate the prediction accuracy of the variables. Results Compared with the non-cure group, the functional cure group had a significantly lower HBsAg level at baseline [21.63 (3.33-157.60) IU/mL vs 794.70 (336.10-1 185.34) IU/mL, Z =-8.869, P 1000 IU/mL (0 vs 8.4%, χ 2 =5.073, P =0.024), a significantly lower level of total bilirubin at baseline [12.60 (10.12-15.93) μmol/L vs 15.50 (11.80-24.10) μmol/L, Z =-3.611, P 2×upper limit of normal (16.5% vs 4.8%, χ 2 =5.835, P =0.016). The multivariate logistic regression analysis showed that baseline HBsAg (odds ratio [ OR ]=0.996, 95% confidence interval [ CI ]: 0.995-0.997, P < 0.001), HBsAg at week 12 of pegylated interferon α-2b treatment ( OR =0.990, 95% CI : 0.986-0.994, P < 0.001), HBsAg at week 24 of pegylated interferon α-2b treatment ( OR =0.983, 95% CI : 0.975-0.991, P < 0.001), and baseline total bilirubin ( OR =0.885, 95% CI : 0.826-0.949, P =0.001) were independent predictive factors for functional cure. The ROC curve of baseline HBsAg showed an AUC of 0.904 and the optimal cut-off value of 118.24 IU/mL; the ROC curve of HBsAg at week 12 of pegylated interferon α-2b treatment showed an AUC of 0.948 and the optimal cut-off value of 73.74 IU/mL; the ROC curve of HBsAg at week 24 of pegylated interferon α-2b treatment showed an AUC of 0.975 and the optimal cut-off value of 11.01 IU/mL; the ROC curve of baseline total bilirubin showed an AUC of 0.664 and the optimal cut-off value of 19.9 μmol/L. Conclusion Baseline HBsAg, HBsAg at week 12 of pegylated interferon α-2b treatment, HBsAg at week 24 of pegylated interferon α-2b, and baseline total bilirubin are independent predictive factors for functional cure at week 48 of pegylated interferon α-2b treatment in CHB patients receiving sequential therapy with NUC and pegylated interferon α-2b.

Effect of Lyophilization on Stability of PEG-Protein Conjugate: A Case Study with Peginterferon alfa-2b

Abstract The purpose of the present study was to develop stable lyophilized formulation of peginterferon alfa-2b which is acquiescent to the short lyophilization process. The present study evaluates the effect of buffering components and cryoprotectant(s) on depegylation of the peginterferon alfa-2b in combination with lyophilization process. Finally, a short lyophilization process was identified which can produce a stable pharmaceutical form of peginterferon alfa-2b without any depegylation during long-term storage. Formulations were analyzed mainly for depegylation by HP-size exclusion chromatography and in-vitro antiviral activity. Residual moisture content in the lyophilized product was also used as a key indicating parameter to check its role with respect to depegylation upon storage under various temperature conditions. It was observed that the peginterferon alfa-2b when formulated in presence of cryoprotectant like sucrose requires longer lyophilization process of about 5 days, irrespective of the buffering components used, to reduce the level of residual moisture content and thereby to produce the stable formulation without depegylation. A stable formulation in presence of high concentration of lactose as a cryoprotectant was developed which can withstand stresses exerted to protein-polymer conjugate during lyophilization phases without any significant depegylation. A short lyophilization process of about 48 hours can be utilized for peginterferon alfa-2b when formulated in presence of lactose as a cryoprotectant through which a stable lyophilized formulation can be produced as against longer process required when sucrose is used a cryoprotectant, which is essential from commercial point of view as lyophilization is a costly process.