Pearls & Oy-sters: A Challenging Optic Neuropathy-What Not to Miss in Optic Nerve Sheath Enhancement.

Optic neuropathies include a wide range of disorders from ischemic, toxic, demyelinating, or inflammatory processes with acute/subacute onset to more gradual compressive or genetic etiologies. Accurate clinical history and multimodality optic nerve imaging including MRI and optical coherence tomography have greatly improved the diagnosis of patients with optic neuropathies. We report a case of a woman with severe monocular visual acuity deficit. Optic nerve sheath enhancement seen on MRI led to a broad differential diagnosis including demyelinating causes, optic nerve sheath meningioma (ONSM), tuberculosis, and sarcoid optic neuropathy. Lack of response to treatment with steroids or plasmapheresis led to biopsy, which confirmed the diagnosis of ONSM.

Neural leprosy investigation using electroneuromyography and the ML Flow rapid test: a case report.

Neural leprosy, which is characterized by nerve involvement without visible skin lesions, presents a diagnostic challenge. This case report examined the significance of diverse diagnostic modalities in the identification of pure neural leprosy. A 28-year-old patient with symptoms of edema, pain, paresthesia, and diminished sensitivity in the lower limbs underwent various tests. A stilt skin smear yielded negative results on bacilloscopy, whereas a Fast ML Flow leprosy test and electroneuromyography supported the diagnosis. This discussion highlights the importance of accessible methods for early investigation. This study emphasizes the multidisciplinary approach and value of the Fast ML Flow leprosy test and electroneuromyography for diagnosing neural leprosy.

Neural leprosy investigation using electroneuromyography and the ML Flow rapid test: a case report

ABSTRACT Neural leprosy, which is characterized by nerve involvement without visible skin lesions, presents a diagnostic challenge. This case report examined the significance of diverse diagnostic modalities in the identification of pure neural leprosy. A 28-year-old patient with symptoms of edema, pain, paresthesia, and diminished sensitivity in the lower limbs underwent various tests. A stilt skin smear yielded negative results on bacilloscopy, whereas a Fast ML Flow leprosy test and electroneuromyography supported the diagnosis. This discussion highlights the importance of accessible methods for early investigation. This study emphasizes the multidisciplinary approach and value of the Fast ML Flow leprosy test and electroneuromyography for diagnosing neural leprosy.

Integrative multi-omics reveals two biologically distinct groups of pilocytic astrocytoma.

Pilocytic astrocytoma (PA), the most common pediatric brain tumor, is driven by aberrant mitogen-activated protein kinase signaling most commonly caused by BRAF gene fusions or activating mutations. While 5-year overall survival rates exceed 95%, tumor recurrence or progression constitutes a major clinical challenge in incompletely resected tumors. Here, we used similarity network fusion (SNF) analysis in an integrative multi-omics approach employing RNA transcriptomic and mass spectrometry-based proteomic profiling to molecularly characterize PA tissue samples from 62 patients. Thereby, we uncovered that PAs segregated into two molecularly distinct groups, namely, Group 1 and Group 2, which were validated in three non-overlapping cohorts. Patients with Group 1 tumors were significantly younger and showed worse progression-free survival compared to patients with group 2 tumors. Ingenuity pathways analysis (IPA) and gene set enrichment analysis (GSEA) revealed that Group 1 tumors were enriched for immune response pathways, such as interferon signaling, while Group 2 tumors showed enrichment for action potential and neurotransmitter signaling pathways. Analysis of immune cell-related gene signatures showed an enrichment of infiltrating T Cells in Group 1 versus Group 2 tumors. Taken together, integrative multi-omics of PA identified biologically distinct and prognostically relevant tumor groups that may improve risk stratification of this single pathway driven tumor type.

Histopathological characterization of cerebral small vessel disease in epilepsy patients with temporal lobe epilepsy submitted to surgery: A case-control study.

BACKGROUND: Cerebrovascular disease (CVD) is a major contributor to epilepsy; however, patients with epilepsy also have a significantly increased risk of stroke. The way in which epilepsy contributes to the increased risk of stroke is still uncertain and is ill-characterized in neuropathological studies. A neuropathological characterization of cerebral small vessel disease (cSVD) in patients with chronic epilepsy was performed. METHODS: Thirty-three patients with refractory epilepsy and hippocampal sclerosis (HS) submitted to epilepsy surgery from a reference center were selected between 2010 and 2020 and compared with 19 autopsy controls. Five randomly selected arterioles from each patient were analyzed using a previously validated scale for cSVD. The presence of CVD disease imaging markers in pre-surgical brain magnetic resonance imaging (MRI) was studied. RESULTS: There were no differences in age (43.8 vs. 41.6 years; p = 0.547) or gender distribution (female gender 60.6% vs. male gender 52.6%; p = 0.575) between groups. Most CVD findings in brain MRI were mild. Patients had a mean time between the epilepsy onset and surgery of 26 ± 14.7 years and were medicated with a median number of three antiseizure medication (ASMs) [IQR 2-3]. Patients had higher median scores in arteriolosclerosis (3 vs. 1; p < 0.0001), microhemorrhages (4 vs. 1; p < 0.0001) and total score value (12 vs. 8.9; p = 0.031) in comparison with controls. No correlation was found between age, number of years until surgery, number of ASMs or cumulative defined daily dosage of ASM. CONCLUSION: The present study provides evidence supporting the increased burden of cSVD in the neuropathological samples of patients with chronic epilepsy.

UBE2C promotes leptomeningeal dissemination and is a therapeutic target in brain metastatic disease.

Background: Despite current improvements in systemic cancer treatment, brain metastases (BM) remain incurable, and there is an unmet clinical need for effective targeted therapies. Methods: Here, we sought common molecular events in brain metastatic disease. RNA sequencing of thirty human BM identified the upregulation of UBE2C, a gene that ensures the correct transition from metaphase to anaphase, across different primary tumor origins. Results: Tissue microarray analysis of an independent BM patient cohort revealed that high expression of UBE2C was associated with decreased survival. UBE2C-driven orthotopic mouse models developed extensive leptomeningeal dissemination, likely due to increased migration and invasion. Early cancer treatment with dactolisib (dual PI3K/mTOR inhibitor) prevented the development of UBE2C-induced leptomeningeal metastases. Conclusions: Our findings reveal UBE2C as a key player in the development of metastatic brain disease and highlight PI3K/mTOR inhibition as a promising anticancer therapy to prevent late-stage metastatic brain cancer.

Medulloblastoma Development in a Patient with a Constitutional Balanced t(5;22)(q35.1;q11.2) Involving the NF2 Gene.

Neurofibromatosis type 2 (NF2) is a brain tumor predisposing syndrome caused by inactivating alterations of the NF2 gene mapped at chromosome 22q. Currently, no genetic information exists on medulloblastomas occurring in NF2 patients. We herein report on the genetic alterations observed in a girl in which the NF2 gene was de novo altered due to a constitutional translocation: t(5;22)(q35.1;q11.2). This girl had a particularly aggressive disease course. At the age of 4, she had already been diagnosed with three lesions classified as schwannomas and a meningioma. At 10 years old, she developed a medulloblastoma. She died at the age of 14 due to a refractory acute myeloid leukemia (AML). From the genetic point of view, we observed that (1) the NF2 gene was rearranged in all patient samples: blood, tumor, and leukemic cells; (2) loss of 3' region of NF2 and the downstream regions of chromosome 22 were only detected in medulloblastoma cells; (3) the known cancer AML-related gene: NPM1 which is mapped at 5q35.1 was not the target of any alteration in our patient. Our data suggest that inactivation of the NF2 gene was relevant for the medulloblastoma pathogenesis. Furthermore, we know that malignant cancers are the result of a multi-epi-genetic sequence of events, and although, unquestionably limited to the genetic findings in one case. We may hypothesize, that as described for a fraction of medulloblastomas, the alteration of a gene mapped at 5q might also have been relevant for medulloblastoma development in our patient.

Inherited myopathies in patients from Sub-Saharan Africa: Results from a retrospective cohort.

The clinical epidemiology of inherited myopathies in sub-Saharan Africa (SSA) is unknown but likely underdiagnosed due to problems of scientific research and social issues. We report a case series of patients born in SSA, evacuated to Portugal through an international health protocol and seen at a single neuromuscular disorders centre, between January/2004 and August/2021. We identified 9 patients (5 males), 35.6 ± 19.3 years-old (10-64), from Cape Verde (n = 4), Angola (n = 2), Sao Tome and Principe (n = 2) and Guinea-Bissau (n = 1), with a delay in diagnosis of 19.7 ± 14.3 years. Seven patients (77.8 %) had positive family history. Most patients had significant morbidity, requiring wheelchair (55.6 %), and nocturnal non-invasive ventilation (55.6 %). The diagnosis included Bethlem myopathy (n = 2), Duchenne muscular dystrophy (n = 2), Emery-Dreifuss muscular dystrophy (n = 1), LGMDR1 (n = 2), LGMDR2 (n = 1), and type-1 myotonic dystrophy (n = 1). Genetic testing was remarkable for 3 mutations previously not described. Despite the small sample, the spectrum of hereditary myopathies in our cohort is like western studies. Further studies are needed to better understand the epidemiology of muscle diseases in SSA.

Impact of brain biopsy on management of nonneoplastic brain disease.

Introduction: Diagnostic yield of brain biopsy in neoplastic brain disease is high and its clinical impact is well established. In nonneoplastic brain disease with negative conventional investigation, decision to undergo invasive procedures is difficult due to its inherent risk and known lower diagnostic yield. Research question: What is the clinical impact of brain biopsy results on management of nonneoplastic brain disease ? Material and methods: A multidisciplinary team retrospectively reviewed and included all nonneoplastic brain disease cases submitted to biopsy between 2009 and 2019, in a tertiary hospital in Lisbon. Baseline characteristics were registered, including immunosuppression status, diagnostic workup, and treatment prior to biopsy. Diagnostic yield, clinical impact and in-hospital complication rates were assessed. Results: Sixty-four patients were included, 20 (31.3%) of them immunosuppressed (15 HIV â€‹+ â€‹patients). Thirty-five (67.7%) were previously treated with steroids or antiinfectious agents, with higher percentage (93.3%) in the immunosuppressed group. Biopsy results were diagnostic in 46 (71.9%) cases. More frequent diagnosis was infectious in 20 (31.2%), neoplastic in 12 (18.8%) and inflammatory diseases in 8 (12.5%). Brain biopsy resulted on impact on patient's clinical management in 56 (87.5%), of which 37(57.8%) were submitted to treatment change. In-hospital complications were registered in 4 (6.6%) patients. Discussion and conclusion: Brain biopsy had clinical impact, including a change in treatment, in most patients studied, and may be considered a useful diagnostic option in nonneoplastic brain disease. However, associated complication rate is not negligible, and previous thorough workup, patient selection and risk-benefit assessment are important.

Patient-derived models of brain metastases recapitulate human disseminated disease.

Dissemination of cancer cells from primary tumors to the brain occurs in many cancer patients, increasing morbidity and death. There is an unmet medical need to develop translational platforms to evaluate therapeutic responses. Toward this goal, we established a library of 23 patient-derived xenografts (PDXs) of brain metastases (BMs) from eight distinct primary tumors. In vivo tumor formation correlates with patients' poor survival. Mouse subcutaneous xenografts develop spontaneous metastases and intracardiac PDXs increase dissemination to the CNS, both models mimicking the dissemination pattern of the donor patient. We test the FDA-approved drugs buparlisib (pan-PI3K inhibitor) and everolimus (mTOR inhibitor) and show their efficacy in treating our models. Finally, we show by RNA sequencing that human BMs and their matched PDXs have similar transcriptional profiles. Overall, these models of BMs recapitulate the biology of human metastatic disease and can be valuable translational platforms for precision medicine.

Características clínicas y angiográficas de pacientes fumadores y no fumadores sometidos a cinecoronariografía - Servicio de Clínica Médica. Hospital Central del Instituto de Previsión Social. Enero 2018 a octubre del 2019

Resumen Introducción: El tabaquismo es considerado uno de los factores de riesgo más importantes en las enfermedades cardiovasculares. La incidencia de pacientes con infarto sigue en aumento, sobre todo en adultos jóvenes en quienes el único factor de riesgo presente es el tabaquismo. Objetivo: Determinar las características clínicas y angiográficas de pacientes fumadores y no fumadores sometidos a cinecoronariografía internados en el servicio de clínica médica de enero 2018 a octubre 2019. Metodología: Estudio observacional, descriptivo, transversal. Se incluirá a todos los pacientes con diagnóstico de infarto de miocardio, que se realizaron cateterismo cardiaco. Resultados: Se incluyó a 100 pacientes, con edad promedio de 67,9± 10,2 años, 39,0% entre 68 y 77 años. 60,0% de sexo masculino. 91,0% presentó hipertension arterial, 42,0% diabetes mellitus, 20,0% dislipidemias, 14,0% obesidad. 62,0% de los pacientes presento sin elevación del segmento ST. En el grupo de pacientes fumadores el 39,1% presentó lesiones de 2 vasos coronarios, entre los no fumadores el 35,0% presentó lesión de 1 vaso. 53,0% se realizó angioplastia con colocacion de stent coronario. Conclusión: Los pacientes fumadores presentan tendencia a la lesión de más de un vaso coronario, el sexo masculino fue predominante, casi todos los pacientes presentaron hipertensión arterial.

Abstract Introduction: Smoking is considered one of the most important risk factors in cardiovascular ediseases. The incidence of heart attack patients continues to increase, especially in young adults in whom the only risk factor present is smoking. Objective: To determine the clinical and angiographic characteristics of smokers and non-smokers patients undergoing coronary angiography admitted to the medical clinic service from January 2018 to October 2019. Methodology: Observational, descriptive, cross-sectional study. All patients diagnosed with myocardial infarction who underwent cardiac catheterization will be included. Results: 100 patients were included, with an average age of 67.9 ± 10.2 years, 39.0% between 68 and 77 years. 60.0% male. 91.0% presented high blood pressure, 42.0% diabetes mellitus, 20.0% dyslipidemia, 14.0% obesity. 62.0% of the patients presented without ST segment elevation. In the group of smoking patients 39.1% presented lesions of 2 coronary vessels, among non-smokers 35.0% presented lesion of 1 vessel. Angioplasty with coronary stent placement was performed 53.0%. Conclusion: Smoking patients have a tendency to damage more than one coronary vessel, the male sex was predominant, almost all patients presented high blood pressure.

Factores de Riesgo de Mortalidad en Pacientes Hematológicos con Aspergilosis Pulmonar en Clínica Médica Instituto de Previsión Social - Hospital Central. Año 2016 A 2018

ResumenIntroducción: Es una de las infecciones oportunistas de mayor impacto en el paciente con patologías hematooncológicas, su detección precoz y tratamiento oportuno impide su diseminación. Objetivo: Determinar factores de riesgo de mortalidad en pacientes hematológicos con aspergilosis pulmonar de pacientes internados en clínica médica en el Instituto de Previsión Social del Hospital Central durante 2016 a 2018. Metodología: Estudio observacional, descriptivo, transversal, se incluyó a pacientes con patologías hematooncológicas e infección por aspergillus internados por un periodo de tres años. Resultados: Se incluyó a 55 pacientes, con edad promedio de 57,2±19,5 años. El 36,3% con edades comprendidas entre 40 a 59 años. 52,8% fue sexo femenino. 56,3% presentó hipertensión arterial. 27,2% linfoma no Hodking. 34,5% se encontraba en fase de mantenimiento al momento del diagnóstico de aspergilosis pulmonar. Respecto al grado de neutropenia el 34,7% presentó neutropenia severa. El 83,6% fue diagnosticado a traves de TACAR y galactomanano. El tiempo de inicio de síntomas hasta el momento del diagnóstico en promedio de días fue de 12,4±4,7 días. 38,1% presentó esputo con aislamiento positivo. Del tratamiento antifúngicos el 78,2% recibió anfotericina B y 21,8% Voriconazol. En relación a la evolución clínica 50,9% fueron alta, el 25,45% requirieron de Unidad de cuidados intensivos, 23,6%obitaron. Conclusión: Las aspergilosis pulmonar se presentó con predominio femenino, la mayoría se encontraba con neutropenia severa en fase de mantenimiento quimioterápico, dos tercios fue tratado con anfotericina B y la mitad fue dado de alta médica.

AbstractIntroduction: It is one of the opportunistic infections with the greatest impact on the patient with hemato-oncological pathologies, its early detection and timely treatment prevents its spread. Objective: To determine risk factors for mortality in hematological patients with pulmonary aspergillosis of patients hospitalized in a medical clinic at the Social Security Institute of the Central Hospital during 2016 to 2018. Methodology: Observational, descriptive, cross-sectional study included patients with hemato-oncological pathologies and infection by aspergillus hospitalized for a period of three years. Results: 55 patients were included, with an average age of 57.2 ± 19.5 years. 36.3% with ages between 40 to 59 years. 52.8% were female. 56.3% presented hypertension. 27.2% non-Hodking lymphoma. 34.5% were in the maintenance phase at the time of pulmonary aspergillosis diagnosis. Regarding the degree of neutropenia, 34.7% presented severe neutropenia. 83.6% were diagnosed through TACAR and galactomannan. Symptom onset time until diagnosis on average days was 12.4 ± 4.7 days. 38.1% presented sputum with positive isolation. Of the antifungal treatment, 78.2% received amphotericin B and 21.8% Voriconazole. In relation to the clinical evolution, 50.9% were high, 25.45% required an intensive care unit, 23.6% obliged. Conclusion: Pulmonary aspergillosis presented with a female predominance, the majority were with severe neutropenia in the phase of chemotherapy maintenance, two thirds were treated with amphotericin B and half were discharged medically.

Allosteric Antagonist Modulation of TRPV2 by Piperlongumine Impairs Glioblastoma Progression.

The use of computational tools to identify biological targets of natural products with anticancer properties and unknown modes of action is gaining momentum. We employed self-organizing maps to deconvolute the phenotypic effects of piperlongumine (PL) and establish a link to modulation of the human transient receptor potential vanilloid 2 (hTRPV2) channel. The structure of the PL-bound full-length rat TRPV2 channel was determined by cryo-EM. PL binds to a transient allosteric pocket responsible for a new mode of anticancer activity against glioblastoma (GBM) in which hTRPV2 is overexpressed. Calcium imaging experiments revealed the importance of Arg539 and Thr522 residues on the antagonistic effect of PL and calcium influx modulation of the TRPV2 channel. Downregulation of hTRPV2 reduces sensitivity to PL and decreases ROS production. Analysis of GBM patient samples associates hTRPV2 overexpression with tumor grade, disease progression, and poor prognosis. Extensive tumor abrogation and long term survival was achieved in two murine models of orthotopic GBM by formulating PL in an implantable scaffold/hydrogel for sustained local therapy. Furthermore, in primary tumor samples derived from GBM patients, we observed a selective reduction of malignant cells in response to PL ex vivo. Our results establish a broadly applicable strategy, leveraging data-motivated research hypotheses for the discovery of novel means tackling cancer.

Seroprevalencia de marcadores para infecciones transmisibles por transfusión en donantes de un hospital de referencia nacional de Paraguay, 2016 / Seroprevalence of markers for transfusion transmitted infections in donors of a national reference hospital of Paraguay, 2016

El uso de los componentes sanguíneos se ha vuelto muy importante para el manejo clínico de diversas patologías, sin embargo, no está exento de complicaciones, una de ellas son las infecciones transmisibles por transfusión (ITT). En las últimas décadas el riesgo de ITT se ha reducido eficazmente gracias a la pesquisa de marcadores serológicos en los donantes. El objetivo del trabajo fue determinar la seroprevalencia de marcadores para infecciones transmitidas por transfusión en donantes de un Hospital de Referencia Nacional de Paraguay durante el año 2016. Este fue un estudio observacional descriptivo de corte transversal. Fueron incluidos todos los pacientes registrados como donantes voluntarios y de reposición que acudieron al hospital durante los meses de enero a diciembre del 2016. La población base estuvo conformado por 21.428 donantes, de los cuales 10.05% presentó pruebas serológicas reactivas. La mediana de edad fue de 32 años, el rango etario más frecuente fue entre 25 a 29 años, el sexo masculino tuvo una frecuencia de 66.89% en los donantes, y el 56.69% de los donantes contaba con seguro médico. El 0.75% fueron donantes voluntarios mientras que el marcador más prevalente fue para sífilis con 5.36%. En relación al Informe del Estado Global de la seguridad de la sangre y su disponibilidad publicado por la Organización Mundial de la Salud (OMS) en el año 2012, los resultados son coherentes con las seroprevalencias dadas por el mismo

The use of blood components has become very important for the clinical management of various pathologies, however, it is not exempt from complications, one of them being transfusion-transmitted infections (TTI). In the last decades, the risk of ITT has been reduced effectively thanks to the screening of serological markers in donors. The objective of this study was to determine the seroprevalence of markers for transfusion-transmitted infections in donors of a national reference hospital of Paraguay during 2016. This was a descriptive observational cross-sectional study with non-probabilistic convenience sampling. All patients registered as voluntary and replacement donors who attended the hospital during the months of January to December 2016 were included. The base population consisted of 21,428 donors, of which 10.05% presented reactive serological tests. The median age was 32 years, the most frequent age range was 25 to 29 years, 66.89% was men, 56.69% of donors had health insurance and 0.75% was voluntary donors. The most prevalent marker was for syphilis (5.36%). In relation to the Report of the Global State of blood safety and its availability published by the World Health Organization (WHO) in 2012, the results are consistent with the prevalence given by this report

Very late-onset limb-girdle muscular dystrophy type 2D: A milder form with a normal muscle biopsy.

Sarcoglycanopathies are a genetically heterogeneous group of autosomal recessive limb-girdle muscular dystrophies (LGMD) caused by mutations in sarcoglycan genes. We report a Portuguese patient with a very late-onset LGMD phenotype, whose muscle biopsy and immunostaining, in particular for α-sarcoglycan, were unrevealing. Muscle MRI showed a predominant, bilateral and symmetric involvement of the tight muscles and also, to a lesser extent, of the posterior compartment of lower legs muscles. Next generation sequencing (NGS) revealed a known homozygous c.850C > T (p.Arg284Cys) mutation in SGCA gene. Milder forms of α-sarcoglycanopathies could be a challenging diagnosis; particularly if muscle histopathology and α-sarcoglycan immunohistochemistry are unhelpful. NGS plays a crucial role not only for aiding in the establishment of a definite diagnosis, but also for expanding clinical presentations.

Mitochondrial Neurogastrointestinal Encephalomyopathy: Novel Pathogenic Mutation in Thymidine Phosphorylase Gene in a Patient from Cape Verde Islands.

Mitochondrial Neurogastrointestinal Encephalomyopathy (MNGIE) is a rare autosomal recessive disorder caused by mutations in the gene encoding the Thymidine Phosphorylase (TP). It is clinically characterized by severe gastrointestinal dysmotility, cachexia, palpebral ptosis, ophthalmoparesis, sensorimotor polyneuropathy and leukoencephalopathy. The diagnosis is established by the presence of typical clinical and neuroimaging features, positive family history, and abnormal genetic test. A 19-year-old Cape Verdean patient with a history since childhood of recurrent episodes of nausea, vomiting, diarrhoea and painful abdominal distension associated with progressive motor disability with difficulty in climbing stairs and running and clumsiness with her hands. The diagnostic workup was suggestive of MNGIE. Genetic screening of the TYMP gene identified a novel mutation (c. 1283 G>A). Patients with MNGIE have significant comorbidity and mortality, and they are frequently misdiagnosed. A better acknowledgment of this disorder is essential to permit an earlier diagnosis and to improve disease management.

Late-onset presentation of POLG1-associated mitochondrial disease.

Mutations in the nuclear POLG1 gene compromise the integrity of mitochondrial DNA and show great allelic and clinical heterogeneity. Among adult POLG1-associated mitochondrial disease, the main clinical feature is chronic progressive external ophthalmoplegia. Other related clinical manifestations are sensory or cerebellar ataxia, peripheral neuropathy, myopathy or extrapyramidal symptoms. We report the case of a 72-year-old man who presented with a late onset sensory neuronopathy, chronic progressive external ophthalmoplegia, gait ataxia and parkinsonism. Genetic studies showed a compound heterozygosity of known pathogenic mutations in the POLG1 gene (variant T252I/P587 L in cis configuration in allele 1 and variant R807C in allele 2). Late life presentation highlights that mitochondrial disorders should be considered regardless of age of onset of symptoms.