Severe infections in systemic necrotizing vasculitis.

Infections in patients with systemic vasculitis represent one of the main causes of mortality. Corticosteroid use, immunosuppressive therapy, age, associated organic involvement and dialysis dependence are risk factors of infection. OBJECTIVES: To determine the prevalence of severe infection and associated factors in patients diagnosed with ANCA-associated vasculitis (AAV) and Polyarteritis Nodosa (PAN). METHODS: retrospective study was conduced in a single rheumatology center (2000-2018). We included patients diagnosed with AAV (Granulomatosis with Polyangiitis (GPA), Eosinophilic Granulomatosis with Polyangiitis (EGPA) and Microscopic Polyangiitis (PAM) and Polyarteritis nodosa (PAN). Serious infectious events requiring hospitalisation or prolonged antibiotic/antiviral treatment, recurrent infection of Herpes Zoster Virus or opportunistic infections were evaluated. Sites of infection, isolated microorganisms and mortality related were analyzed. RESULTS: 105 patients were analyzed, follow-up time median 18 m, 58.7% were women and median age was 52 years. Types of vasculitis: 41.9% PAM, 16.2% EPGA, 40% GPA, 1.9% PAN. Constitutional, pulmonary, renal and otorhinolaryngology manifestations were the most frequent. PREVALENCE OF INFECTION: 34.2%, with a median of 3 months from diagnosis of vasculitis to the infectious event. Low respiratory tract (42.8%), sepsis (31.4%), and urinary tract (14.3%) were the most common sites of infections. Bacterial aetiology was the most prevalent (67.7%). Mortality at the first event was 14.3% and a 72.2% of patients were in the induction phase of treatment. Infectious events were significantly associated with age > 65 years (p = 0.030), presence of lung (p = 0.016) and renal involvement (p = 0.001), BVASv3 > 15, mortality (p = 0.0002). CONCLUSIONS: The prevalence of infection was 34.2%. Lower airway infections, septicemia and urinary tract infections were the most prevalent. Infections were associated with renal and pulmonary involvement, age older than 65 years and score BVAS > 15. Severe infections were associated with mortality, especially in elderly patients.

A novel anti-apoptotic role for Cdc42/ACK-1 signaling in neurons.

Neurodegenerative diseases such as amyotrophic lateral sclerosis, Alzheimer's and Parkinson's disease are caused by a progressive and aberrant destruction of neurons in the brain and spinal cord. These disorders lack effective long-term treatments that impact the underlying mechanisms of pathogenesis and as a result, existing options focus primarily on alleviating symptomology. Dysregulated programmed cell death (i.e., apoptosis) is a significant contributor to neurodegeneration, and is controlled by a number of different factors. Rho family GTPases are molecular switches with recognized importance in proper neuronal development and migration that have more recently emerged as central regulators of apoptosis and neuronal survival. Here, we investigated a role for the Rho GTPase family member, Cdc42, and its downstream effectors, in neuronal survival and apoptosis. We initially induced apoptosis in primary cultures of rat cerebellar granule neurons (CGNs) by removing both growth factor-containing serum and depolarizing potassium from the cell medium. We then utilized both chemical inhibitors and adenoviral shRNA targeted to Cdc42 to block the function of Cdc42 or its downstream effectors under either control or apoptotic conditions. Our in vitro studies demonstrate that functional inhibition of Cdc42 or its downstream effector, activated Cdc42-associated tyrosine kinase-1 (ACK-1), had no adverse effects on CGN survival under control conditions, but significantly sensitized neurons to cell death under apoptotic conditions. In conclusion, our results suggest a key pro-survival role for Cdc42/ACK-1 signaling in neurons, particularly in regulating neuronal susceptibility to pro-apoptotic stress such as that observed in neurodegenerative disorders.

Immunocal® limits gliosis in mouse models of repetitive mild-moderate traumatic brain injury.

Successive traumatic brain injuries (TBIs) exacerbate neuroinflammation and oxidative stress. No therapeutics exist for populations at high risk of repetitive mild TBIs (rmTBIs). We explored the preventative therapeutic effects of Immunocal®, a cysteine-rich whey protein supplement and glutathione (GSH) precursor, following rmTBI and repetitive mild-moderate TBI (rmmTBI). Populations that suffer rmTBIs largely go undiagnosed and untreated; therefore, we first examined the potential therapeutic effect of Immunocal® long-term following rmTBI. Mice were treated with Immunocal® prior to, during, and following rmTBI induced by controlled cortical impact until analysis at 2 weeks, 2 months, and 6 months following the last rmTBI. Astrogliosis and microgliosis were measured in cortex at each time point and edema and macrophage infiltration by MRI were analyzed at 2 months post-rmTBI. Immunocal® significantly reduced astrogliosis at 2 weeks and 2 months post-rmTBI. Macrophage activation was observed at 2 months post-rmTBI but Immunocal® had no significant effect on this endpoint. We did not observe significant microgliosis or edema after rmTBI. The dosing regimen was repeated in mice subjected to rmmTBI; however, using this experimental paradigm, we examined the preventative therapeutic effects of Immunocal® at a much earlier timepoint because populations that suffer more severe rmmTBIs are more likely to receive acute diagnosis and treatment. Increases in astrogliosis, microgliosis, and serum neurofilament light (NfL), as well as reductions in the GSH:GSSG ratio, were observed 72 h post-rmmTBI. Immunocal® only significantly reduced microgliosis after rmmTBI. In summary, we report that astrogliosis persists for 2 months post-rmTBI and that inflammation, neuronal damage, and altered redox homeostasis present acutely following rmmTBI. Immunocal® significantly limited gliosis in these models; however, its neuroprotection was partially overwhelmed by repetitive injury. Treatments that modulate distinct aspects of TBI pathophysiology, used in combination with GSH precursors like Immunocal®, may show more protection in these repetitive TBI models.

Recomendaciones de la Sociedad Argentina de Reumatología en el manejo de la arteritis de células gigantes / Recommendations of the Argentine Society of Rheumatology in the management of giant cell arteritis

La arteritis de células gigantes (ACG) es una vasculitis sistémica que afecta a personas adultas; compromete vasos arteriales de mediano y gran calibre, con potenciales complicaciones de gravedad, como la ceguera, y es considerada una emergencia médica. El objetivo de estas guías fue desarrollar las primeras recomendaciones argentinas para su tratamiento, basadas en la revisión de la literatura mediante metodología GRADE. Un panel de expertos en vasculitis elaboró las preguntas en formato PICO (población, intervención, comparador y outcomes), y luego un panel de expertos en metodología efectuó la revisión de la bibliografía con la extracción de la evidencia para cada una de las preguntas. Se realizó un focus group de pacientes para conocer sus preferencias y experiencias. Finalmente, con la información recabada, el panel de expertos en vasculitis procedió a la votación de las recomendaciones que a continuación se presentan.

Giant cell arteritis (GCA) is a systemic vasculitis affecting adult patients and involving large and medium vessels. Potential serious complications as blindness may occur and it is considered a medical emergency. The objective of elaborating this guideline was to develop first Argentinian GCA treatment recommendations using GRADE methodology. An expert panel generated clinically meaningful questions addressing aspects of the treatment of GCA in the Population, Intervention, Comparator and Outcome (PICO) format and then a group of methodology experts reviewed and extracted data from literature summarizing available evidence. A patient's focus group discussion took place gathering information on their preferences and experiences. Finally, the vasculitis expert panel, with all the information obtained, voted recommendations here presented.

Guías Argentinas de Vasculitis Suplemento. Tablas arteritis de células gigantes / Argentine Vasculitis Guidelines Supplement. Giant cell arteritis tables

La arteritis de células gigantes (ACG) es una vasculitis sistémica que afecta a personas adultas; compromete vasos arteriales de mediano y gran calibre, con potenciales complicaciones de gravedad, como la ceguera, y es considerada una emergencia médica. El objetivo de estas guías fue desarrollar las primeras recomendaciones argentinas para su tratamiento, basadas en la revisión de la literatura mediante metodología GRADE. Un panel de expertos en vasculitis elaboró las preguntas en formato PICO (población, intervención, comparador y outcomes), y luego un panel de expertos en metodología efectuó la revisión de la bibliografía con la extracción de la evidencia para cada una de las preguntas. Se realizó un focus group de pacientes para conocer sus preferencias y experiencias. Finalmente, con la información recabada, el panel de expertos en vasculitis procedió a la votación de las recomendaciones que a continuación se presentan.

Preliminary identification of pathogenic variants in an Afro-Colombian Raizal family with risk factors for glaucoma / Identificación preliminar de variantes patógenas en una familia raizal afrocolombiana con factores de riesgo para glaucoma

Abstract Objective: To identify pathogenic variants in an Afro-Colombian Raizal family with risk factors for glaucoma. Methods: In the present study, whole exome sequencing was performed on seven members of a Raizal family from the archipelago of San Andrés, Providencia, and Santa Catalina, in the Caribbean region of Colombia. Four of them had been diagnosed with glaucoma. In addition, two healthy volunteers from the island were included. Results: Of the 198 single nucleotide variants associated with glaucoma, previously reported by the DisGeNET database, four were identified in members of the Raizal family: rs11938093, rs7336216, rs3817672, and rs983034. Furthermore, single nucleotide variant rs983034 was identified in the Wnt ligand secretion mediator gene in all members of the family but not in healthy volunteers. Notably, WLS dysfunctions have been linked to pathology in the trabecular meshwork of the eye. Trabecular meshwork is an important regulator of the outflow of aqueous humor that maintains intraocular pressure (intraocular pressure) at normal levels. Damage to trabecular meshwork is associated with ocular hypertension, which leads to glaucoma progression. In relation to the other single nucleotide variants that were identified, their presence was confirmed in some members of the Raizal family. However, it is still unclear the pathophysiological cause that associates these single nucleotide variants with glaucoma. Conclusions: It was possible to identify four non-synonymous single nucleotide variants that predict significant damage to the structure and function of genes associated with glaucoma pathology in an Afro-Colombian.

Resumen Objetivo: Identificar las variantes patogénicas en una familia raizal afrocolombiana con factores de riesgo para el glaucoma. Métodos: En el presente estudio, se realizó una secuenciación de exoma completo en siete miembros de una familia Raizal del archipiélago de San Andrés, Providencia y Santa Catalina del Caribe colombiano. La mitad de ellos habían sido diagnosticados con glaucoma. Además, se incluyeron dos voluntarios sanos de la isla. Resultados: De las 198 variantes de un solo nucleótido (SNV) asociadas con el glaucoma, previamente informadas por la base de datos DisGeNET, se identificaron cuatro en los miembros de la familia Raizal: rs11938093, rs7336216, rs3817672 y rs983034. Ademas, en todos los miembros de la familia, pero no en voluntarios sanos, se identificó SNV rs983034 en el gen mediador de secreción de ligando Wnt (WLS). Notablemente, las disfunciones WLS se han relacionado con patologías en la red trabecular (TM) del ojo. TM es un regulador importante del flujo de salida del humor acuoso que mantiene la presión intraocular (presión intraocular) en niveles normales. El daño a la TM se asocia con hipertensión ocular que conduce a la progresión del glaucoma. En relación con los demás SNV identificados, se constató su presencia en algunos miembros de la familia Raizal. Sin embargo, aún no está clara la causa fisiopatológica que asocia estas SNV con el glaucoma. Conclusiones: Fue posible identificar cuatro SNVs no sinónimos con predicción de daño significativo en la estructura y función de genes asociados a patología de glaucoma en un afrocolombiano.

Omics in the detection and identification of biosynthetic pathways related to mycotoxin synthesis.

Mycotoxins are secondary metabolites that are known to be toxic to humans and animals. On the other hand, some mycotoxins and their analogues possess antioxidant as well as antitumor properties, which could be relevant in the fields of pharmaceutical analysis and food research. Omics techniques are a group of analytical tools applied in the biological sciences in order to study genes (genomics), mRNA (transcriptomics), proteins (proteomics), and metabolites (metabolomics). Omics have become a vital tool in the field of mycotoxins, especially contributing to the identification of biomarkers with potential use for the detection of mycotoxigenic species and the gathering of information about the biosynthetic pathways of mycotoxins in different environments. This approach has provided tools for the development of prevention strategies and control measures for different mycotoxins. Additionally, research has revealed important information about the impact of global warming and climate change on the prevalence of mycotoxin issues in society. In the context of foodomics, the aim is to apply omics techniques in order to ensure food safety. The objective of the present review is to determine the state of the art regarding the development of analytical techniques based on omics in the identification of biosynthetic pathways related to mycotoxin synthesis.

Vasculitis cutáneas: etiología y características clínicas en pacientes adultos en un centro de tercer nivel / Cutaneous vasculitis: etiology and clinical characteristics in adult patients at a third-level center

Introducción: Diversas entidades clínicas, como enfermedades autoinmunes, infecciones, neoplasias y fármacos pueden manifestarse con lesiones vasculíticas en la piel. Debido a la heterogeneidad de las causas, suelen representar un desafío diagnóstico. El objetivo de este estudio es describir la etiología de las vasculitis cutáneas (VC) y evaluar las características clínicas, histológicas y de laboratorio halladas en estos pacientes. Material y métodos: Se realizó un estudio retrospectivo con revisión de historias clínicas de pacientes mayores de 16 años con VC por diagnóstico clínico y/o histológico evaluados en el período 2010-2018. Resultados: Se incluyeron 74 pacientes. El 69% son mujeres con una edad media al diagnóstico de 41 años (DE 16.5, rango 16-75). Las causas más frecuentes asociadas a las VC fueron las enfermedades autoinmunes (EAI) en un 50% de los pacientes evaluados. En el 29.7% de los casos no pudo identificarse una causa subyacente. En el 2.7% de los casos se asoció a neoplasias, otro 2.7% a fármacos y un 12% a otras etiologías. El 76% de los pacientes presentaron formas clínicas no severas, predominando la púrpura palpable en el 65% de los casos. Entre los pacientes biopsiados, el 76% fueron vasculitis leucocitoclásticas (VLC). Como manifestaciones extracutáneas asociadas, predominó el compromiso articular (43,2%). En las vasculitis asociadas a EAI, el 33 % presentó compromiso renal, en tanto que éste no se observó en ninguno de los pacientes con vasculitis idiopáticas. El 78% de los pacientes recibieron glucocorticoides sistémicos. Conclusión: En nuestro centro, la etiología más común de VC fue la asociada a EAI. La mayoría de los pacientes eran mujeres. Clínicamente predominaron las manifestaciones cutáneas no severas y la VLC fue el hallazgo más frecuente en las biopsias.

Background: Various clinical entities, such as autoimmune diseases, infections, neoplasms and drugs can manifest with vasculitic lesions on the skin. Due to the heterogeneity of causes, they often represent a diagnostic challenge. The aim of this study is to describe the etiology of cutaneous vasculitis (CV) and to assess the clinical, histological and laboratory characteristics found in these patients. Material and methods: A retrospective study was carried out with a review of the medical records of patients over 16 years old with CV by clinical and/or histological diagnosis evaluated in the period 2010-2018. Results: 74 patients were included. 69% are women with a mean age at diagnosis of 41 years (SD 16.5, range 16-75). The most frequent causes associated with CVs were autoimmune diseases (AID) in 50% of the patients evaluated. In 29.7% of the cases, an underlying cause could not be identified. In 2.7% of the cases it was associated with neoplasms, another 2.7% with drugs, and 12% with other etiologies. 76% of the patients presented non-severe clinical forms, with palpable purpura predominant in 65% of the cases. Among the biopsied patients, 76% were leukocytoclastic vasculitis (LCV). As associated extracutaneous manifestations, joint involvement predominated (43.2%). In vasculitis associated with AID, 33% presented renal involvement, while this was not observed in any of the patients with idiopathic vasculitis. 78% of the patients received systemic glucocorticoids. Conclusion: In our center, the most common etiology of CV was associated with AID. Most of the patients were women. Clinically, non-severe skin manifestations predominated and VLC was the most frequent finding in biopsies.

Estado de situación de la investigación en salud en materia de intervenciones preventivas y terapéuticas, seguras y eficaces, en COVID-19. Provincia de Buenos Aires años 2020-2022 / Estado de situación de la investigación en salud en materia de intervenciones preventivas y terapéuticas, seguras y eficaces, en COVID-19. Provincia de Buenos Aires años 2020-2022

INTRODUCCIÓN La pandemia producida por el virus SARS-CoV-2 ha puesto en marcha diversos protocolos de investigación clínica, con el fin de obtener resultados en materia de estrategias preventivas y terapéuticas en COVID-19. OBJETIVO Describir el estado de situación del campo de la investigación en salud en materia de intervenciones preventivas y terapéuticas, seguras y eficaces, en COVID-19 en el ámbito público, privado y de obra social de Buenos Aires contempladas en la Ley11044 y su decreto reglamentario. MÉTODOS Se analizaron los estudios preventivos y terapéuticos en COVID-19 autorizados y registrados por la Comisión Conjunta de Investigaciones en Salud durante el período comprendido entre marzo 2020 y mayo 2022 a través de un estudio observacional, descriptivo, transversal, retrospectivo y prospectivo. La informació recolectada se cargó en matriz de datos diseñada y se empleó para la recuperación procesamiento y análisis estadístico el software SPSS (versión 25) y Epi-Info versión para Windows (Center for Disease Control and Prevention, Atlanta, GA, USA). RESULTADOS Se registraron 51 protocolos de intervención y 21 (41,2%) fueron incorporados para el análisis de datos. El 61,9% focalizó su objetivo en la estrategia de tratamiento, y un 14,3% en la estrategia de prevención o ambas estrategias (23,8%). Las intervenciones más estudiadas fueron agentes biológicos monoclonales, inhibidores de Janus Kinasa, vacunas, antivirales e interferón. El 90,5% reportaron ser seguras, y e 71,4% cumplieron con sus criterios de eficacia. Finalmente, 29,7% fue la incidencia de los estudios de intervención respecto del total de estudios en COVID-19 registrados. Discusión El presente trabajo genera una primera aproximación a la situación actual de la investigación del SARS-CoV-2 en la provincia de Buenos Aires y a las diferentes estrategias de tratamiento, brindando evidencia científica para la formulación d políticas sanitarias, como así también recomendaciones en salud pública y a la práctica clínica.

Optic nerve coloboma as extension of the phenotype of 22q11.23 duplication syndrome: a case report.

BACKGROUND: 22q11.2 duplication syndrome (Dup22q11.2) has reduced penetrance and variable expressivity. Those affected may have intellectual disabilities, dysmorphic facial features, and ocular alterations such as ptosis, hypertelorism, nystagmus, and chorioretinal coloboma. The prevalence of this syndrome is unknown, there are only approximately 100 cases reported. However Dup22q11.2 should have a similar prevalence of DiGeorge syndrome (1 in each 4000 new-borns), in which the same chromosomal region that is duplicated in Dup22q11.2 is deleted. CASE PRESENTATION: We report a patient with intellectual disability, psychomotor development delay, hearing loss with disyllable pronunciation only, hyperactivity, self-harm, hetero-aggressive behaviour, facial dysmorphism, left facial paralysis, post-axial polydactyly, and for the first time in patients with Dup22q11.2, optic nerve coloboma and dysplasia in optic nerve. Array comparative genomic hybridization showed a 22q11.23 duplication of 1.306 million base pairs. CONCLUSIONS: New ocular findings in Dup22q11.2 syndrome, such as coloboma and dysplasia in the optic nerve, are reported here, contributing to the phenotypic characterization of a rarely diagnosed genetic syndrome. A complete characterization of the phenotype is necessary to increase the rate of clinical suspicion and then the genetic diagnostic. In addition, through bioinformatics analysis of the genes mapped to the 22q11.2 region, it is proposed that deregulation of the SPECC1L gene could be implicated in the development of ocular coloboma.

Protocatechuic Acid Extends Survival, Improves Motor Function, Diminishes Gliosis, and Sustains Neuromuscular Junctions in the hSOD1G93A Mouse Model of Amyotrophic Lateral Sclerosis.

Amyotrophic lateral sclerosis (ALS) is a devastating disorder characterized by motor neuron apoptosis and subsequent skeletal muscle atrophy caused by oxidative and nitrosative stress, mitochondrial dysfunction, and neuroinflammation. Anthocyanins are polyphenolic compounds found in berries that possess neuroprotective and anti-inflammatory properties. Protocatechuic acid (PCA) is a phenolic acid metabolite of the parent anthocyanin, kuromanin, found in blackberries and bilberries. We explored the therapeutic effects of PCA in a transgenic mouse model of ALS that expresses mutant human Cu, Zn-superoxide dismutase 1 with a glycine to alanine substitution at position 93. These mice display skeletal muscle atrophy, hindlimb weakness, and weight loss. Disease onset occurs at approximately 90 days old and end stage is reached at approximately 120 days old. Daily treatment with PCA (100 mg/kg) by oral gavage beginning at disease onset significantly extended survival (121 days old in untreated vs. 133 days old in PCA-treated) and preserved skeletal muscle strength and endurance as assessed by grip strength testing and rotarod performance. Furthermore, PCA reduced astrogliosis and microgliosis in spinal cord, protected spinal motor neurons from apoptosis, and maintained neuromuscular junction integrity in transgenic mice. PCA lengthens survival, lessens the severity of pathological symptoms, and slows disease progression in this mouse model of ALS. Given its significant preclinical therapeutic effects, PCA should be further investigated as a treatment option for patients with ALS.

Asociación entre Artritis Reumatoidea y otras enfermedades autoinmunes / Association between Rheumatoid Arthritis and other autoimmune diseases

Objetivos: Determinar la frecuencia de enfermedades autoinmunes (EAI) en pacientes con Artritis Reumatoidea (AR) y comparar la frecuencia de EAI entre pacientes con AR y sin AR ni otra EAI reumatológica. Material y Métodos: Estudio multicéntrico, observacional, analítico, retrospectivo. Se incluyeron pacientes consecutivos con AR (ACR/EULAR 2010) y como grupo control pacientes con diagnóstico inicial de Osteoartritis primaria (OA). Resultados: Se incluyeron 1549 pacientes: 831 con AR (84% mujeres, edad media 55.2 años [DE 13.6]) y 718 con OA (82% mujeres, edad media 67 años [DE 11.1]). La frecuencia de EAI en el grupo AR fue del 22% (n=183). Estos presentaron mayor frecuencia de EAI reumatológicas (9.4 vs 3.3%, p< 0.001), y menor frecuencia de EAI no reumatológicas que aquellos con OA (15.3 vs 20.5, p=0.007). La EAI reumatológica más prevalente fue el Síndrome de Sjögren, el cual fue más frecuente en el grupo AR (87.2 vs 29.2%, p< 0,001). La frecuencia de EAI reumatológicas en los pacientes con AR fue mayor en la forma erosiva (11 vs 6.8%, p=0.048). Conclusión: La frecuencia de EAI en los pacientes con AR fue del 22%, en quienes predominaron las de etiología reumatológica mientras que, las no reumatológicas predominaron en pacientes con OA.

Objectives: To determine the frequency of autoimmune diseases (AID) in Rheumatoid Arthritis (RA) patients and to compare this frequency between patients with and without RA or other rheumatologic AID. Methods: Multicenter, observational, analytical, retrospective study. Consecutive patients with diagnosis of RA (ACR/EULAR 2010) were included. Patients with initial diagnosis of primary ostearthritis (OA) were used as control group. Results: A total of 1549 patients were included: 831 RA (84% women, mean age 55.2 [±13.6]) and 718 OA (82% women, mean age 67 [± 11.1]). The frequency of AID in the RA group was 22% (n=183). RA patients showed higher frequency of rheumatologic AID (9.4 vs 3.3%, p< 0.001), and lower frequency of non-rheumatologic AID than OA patients (15.3 vs 20.5%, p= 0.007). The most prevalent rheumatic AID was Sjögren's Syndrome, which was more frequent in the AR group (87.2 vs 29.2%, p<0.001). The frequency of rheumatologic AID in RA patients was higher in those with erosive RA (11 vs 6.8%, p=0.048). Conclusion: The frequency of AID in RA patients was 22%. Rheumatologic AID were more frequent in RA patients, whereas non-rheumatologic AID prevailed in OA patients.

Lesiones destructivas de la línea media: diagnóstico diferencial con Vasculitis Asociada a ANCA / Destructive lesions of midline: differential diagnosis with ANCA-associated Vasculitis

Presentamos los casos clínicos de tres pacientes adultos jóvenes de origen boliviano, que fueron hospitalizados en salas de clínica médica de un hospital de tercer nivel por manifestaciones de la vía aérea superior y lesiones de las estructuras de la línea media. Reumatología evaluó la posibilidad del diagnóstico de Vasculitis asociada a ANCA, la cual es un diagnóstico diferencial de la entidad conocida como "lesión destructiva de la línea media". En todos los casos se arribó al diagnóstico definitivo de Linfoma T luego de un exhaustivo estudio histopatológico.

We present clinical cases of three Bolivian young adults who were hospitalized in the medical clinic rooms of a third level hospital for upper airway manifestation and lesions of the midline structures. Rheumatology service evaluated the diagnosis of ANCA associated Vasculitis, which is a differential diagnosis of the entity known as midline destructive lesion. In all cases, the final diagnosis of T lymphoma was reached after an exhaustive histopathological study.

Dysregulation of Rac or Rho elicits death of motor neurons and activation of these GTPases is altered in the G93A mutant hSOD1 mouse model of amyotrophic lateral sclerosis.

Rho GTPases play a central role in neuronal survival; however, the antagonistic relationship between Rac and Rho in the regulation of motor neuron survival remains poorly defined. In the current study, we demonstrate that treatment with NSC23766, a selective inhibitor of the Rac-specific guanine nucleotide exchange factors, Tiam1 and Trio, is sufficient to induce the death of embryonic stem cell (ESC)-derived motor neurons. The mode of cell death is primarily apoptotic and is characterized by caspase-3 activation, de-phosphorylation of ERK5 and AKT, and nuclear translocation of the BH3-only protein Bad. As opposed to the inhibition of Rac, motor neuron cell death is also induced by constitutive activation of Rho, via a mechanism that depends on Rho kinase (ROCK) activity. Investigation of Rac and Rho in the G93A mutant, human Cu, Zn-superoxide dismutase (hSOD1) mouse model of amyotrophic lateral sclerosis (ALS), revealed that active Rac1-GTP is markedly decreased in spinal cord motor neurons of transgenic mice at disease onset and end-stage, when compared to age-matched wild type (WT) littermates. Furthermore, although there is no significant change in active RhoA-GTP, total RhoB displays a striking redistribution from motor neuron nuclei in WT mouse spinal cord to motor neuron axons in end-stage G93A mutant hSOD1 mice. Collectively, these data suggest that the intricate balance between pro-survival Rac signaling and pro-apoptotic Rho/ROCK signaling is critical for motor neuron survival and therefore, disruption in the balance of their activities and/or localization may contribute to the death of motor neurons in ALS.

Development of an analytical methodology for the determination of organochlorine pesticides by ethylene-vinyl acetate passive samplers in marine surface waters based on ultrasound-assisted solvent extraction followed with headspace solid-phase microextraction and gas chromatography-tandem mass spectrometry.

A novel strategy for the analysis of 20 organochlorine pesticides (OCPs) monitoring in marine surface waters through ethylenevinyl acetate (EVA) passive samplers was developed and validated. The approach is based on the coupled of ultrasound-assisted solvent extraction (UASE) and headspace solid-phase microextraction (HS-SPME) as extraction method for OCPs from EVA samplers. The UASE-HS-SPME method was optimized with a 27-4 Plackett-Burman design, while the significant factors (salting out, temperature and extraction time) were optimized using a central composite design (CCD) combined with desirability function (DF). The OCPs detection was performed using multiple reaction monitoring (MRM) by gas chromatography-tandem mass spectrometry (GC-MS/MS). The optimum experimental conditions comprised: salting out: 23% wv-1 NaCl, temperature: 75°C and extraction time: 55 min. The optimized method was validated in terms of linearity (R2>0.9946), recovery (>61%) and inter-day and intra-day reproducibility (<19%) for 20 OCPs studied. The limits of detection (LODs) were ranging from 0.01 ng for α-hexachlorocyclohexane and 0.27 ng for endrin aldehyde. Finally, the methodology was tested in marine surface seawater of Southern Chile using EVA samplers, where twelve OCPs were detected at ultra-trace levels (ngL-1).

Paracoccidioidomicosis. Una enfermedad multisistémica / Paracoccidioidomycosis. A multisystemic disease

Resumen La paracoccidioidomicosis es una enfermedad crónica, sistémica y progresiva, sólo descrita en América Latina. Su presentación clínica crónica multifocal es la más prevalente, afectando mayormente a hombres adultos y comprometiendo principalmente a pulmones, sin embargo, puede diseminarse a cualquier órgano generando múltiples complicaciones en el paciente. Presentamos el caso de un paciente masculino, inmunocompetente, caficultor, quien debuta con compromiso de la glándula suprarrenal y en quien posteriormente se documenta compromiso pulmonar. El diagnóstico se confirmó mediante biopsia de lesiones en glándula suprarrenal, inmunodifusión en gel de agar y reacción en cadena de la polimerasa, la cual mostró compromiso por Paracoccidioides brasiliensis. (Acta Med Colomb 2018; 43: 111-114).

Abstract Paracoccidioidomycosis is a chronic, systemic and progressive disease which is described only in Latin America. Its chronic and multifocal clinical presentation is the most prevalent, affecting mainly adult men and compromising mainly lungs; however, it can spread to any organ generating multiple complications in the patient. The case of an immunocompetent male patient, coffee grower, who debuted with compromise of the adrenal gland and in who subsequently pulmonary involvement was documented, is presented. The diagnosis was confirmed by biopsy of lesions in the adrenal gland, agar gel immunodiffusion and polymerase chain reaction, which showed compromise by Paracoccidioides brasilensis. (Acta Med Colomb 2018; 43: 111-114).

Structural and evolutionary analyses show unique stabilization strategies in the type IV pili of Clostridium difficile.

Type IV pili are produced by many pathogenic Gram-negative bacteria and are important for processes as diverse as twitching motility, biofilm formation, cellular adhesion, and horizontal gene transfer. However, many Gram-positive species, including Clostridium difficile, also produce type IV pili. Here, we identify the major subunit of the type IV pili of C. difficile, PilA1, and describe multiple 3D structures of PilA1, demonstrating the diversity found in three strains of C. difficile. We also model the incorporation of both PilA1 and a minor pilin, PilJ, into the pilus fiber. Although PilA1 contains no cysteine residues, and therefore cannot form the disulfide bonds found in all Gram-negative type IV pilins, it adopts unique strategies to achieve a typical pilin fold. The structures of PilA1 and PilJ exhibit similarities with the type IVb pilins from Gram-negative bacteria that suggest that the type IV pili of C. difficile are involved in microcolony formation.

Recovery from experimental parkinsonism by semaphorin-guided axonal growth of grafted dopamine neurons.

Cell therapy in animal models of Parkinson's disease (PD) is effective after intrastriatal grafting of dopamine (DA) neurons, whereas intranigral transplantation of dopaminergic cells does not cause consistent behavioral recovery. One strategy to promote axonal growth of dopaminergic neurons from the substantia nigra (SN) to the striatum is degradation of inhibitory components such as chondroitin sulphate proteoglycans (CSPG). An alternative is the guidance of DA axons by chemotropic agents. Semaphorins 3A and 3C enhance axonal growth of embryonic stem (ES) cell-derived dopaminergic neurons in vitro, while Semaphorin 3C also attracts them. We asked whether intranigral transplantation of DA neurons, combined with either degradation of CSPG or with grafts of Semaphorin 3-expressing cells, towards the striatum, is effective in establishing a new nigrostriatal dopaminergic pathway in rats with unilateral depletion of DA neurons. We found depolarization-induced DA release in dorsal striatum, DA axonal projections from SN to striatum, and concomitant behavioral improvement in Semaphorin 3-treated animals. These effects were absent in animals that received intranigral transplants combined with Chondroitinase ABC treatment, although partial degradation of CSPG was observed. These results are evidence that Semaphorin 3-directed long-distance axonal growth of dopaminergic neurons, resulting in behavioral improvement, is possible in adult diseased brains.

Axon responses of embryonic stem cell-derived dopaminergic neurons to semaphorins 3A and 3C.

Class 3 Semaphorins are a subfamily of chemotropic molecules implicated in the projection of dopaminergic neurons from the ventral mesencephalon and in the formation of the nigrostriatal pathway (NSP) during embryonic development. In humans, loss of mesencephalic dopaminergic neurons leads to Parkinson's disease (PD). Cell replacement therapy with dopaminergic neurons generated from embryonic stem cells (ES-TH(+)) is being actively explored in models of PD. Among several requisites for this approach to work are adequate reconstruction of the NSP and correct innervation of normal striatal targets by dopaminergic axons. In this work, we characterized the response of ES-TH(+) neurons to semaphorins 3A, 3C, and 3F and compared it with that of tyrosine hidroxylase-positive neurons (TH(+)) obtained from embryonic ventral mesencephalon (VM-TH(+)). We observed that similar proportions of ES-TH(+) and VM-TH(+) neurons express semaphorin receptors neuropilins 1 and 2. Furthermore, the axons of both populations responded very similarly to semaphorin exposure: semaphorin 3A increased axon length, and semaphorin 3C attracted axons and increased their length. These effects were mediated by neuropilins, insofar as addition of blocking antibodies against these proteins reduced the effects on axonal growth and attraction, and only TH(+) axons expressing neuropilins responded to the semaphorins analyzed. The observations reported here show phenotypic similarities between VM-TH(+) and ES-TH(+) neurons and suggest that semaphorins 3A and 3C could be employed to guide axons of grafted ES-TH(+) in therapeutic protocols for PD.

Características do tipo de alimentação e da fala de crianças com e sem apinhamento dentário / Characteristics of food consistence and speech production in children with normal occlusion and malocclusion related to tooth crowding

OBJETIVO: caracterizar o tipo de consistência alimentar e a articulação da fala em crianças com oclusão normal e com apinhamento dentário, verificando-se possíveis correlações e interferências. MÉTODOS: participaram 60 crianças, de ambos os sexos, entre 7 e 12 anos, divididas em dois grupos. G1: 30 crianças com apinhamento dentário, G2: 30 crianças sem apinhamento dentário, conforme avaliação odontológica. Foram critérios de exclusão: déficits neurológicos e cognitivos, presença de hábitos orais, respiração oral crônica, deformações dentofaciais, realização de tratamento ortopédico/ortodôntico e/ou fonoaudiológico. Foram realizadas: avaliação do sistema estomatognático; avaliação odontológica quanto à situação dento-oclusal; aplicação de questionários aos pais visando contemplar critérios de exclusão e definir os hábitos alimentares quanto à sua consistência; avaliação de fala quanto à produção fonética e fonológica. RESULTADOS: crianças sem apinhamento dentário têm alimentação predominantemente dura, enquanto aquelas com apinhamento dentário têm alimentação predominantemente amolecida; caracterizada principalmente pelo hábito de ingestão de líquido na presença do alimento na boca. Quanto à fala, não foram encontradas alterações significativas independente do apinhamento dentário e do tipo de consistência alimentar. CONCLUSÃO: há indícios de que a presença do apinhamento dentário relaciona-se à consistência alimentar. A alimentação amolecida parece constituir provável fator etiológico ou contribuinte à existência do apinhamento dentário. O tipo de alimentação e a presença de apinhamento dentário parecem não interferir na articulação da fala.

PURPOSE: to characterize the kind of food consistence and speech production in children with normal occlusion and malocclusion related to tooth crowding, as well as to verify possible correlations and interferences. METHODS: sixty children from 7 to 12 years old, both genders, divided in two groups: (G1) formed by thirty children with tooth crowding and (G2), the control group, formed by thirty children without tooth crowding. Exclusion criteria: neurological or cognitive problems, oral habits, mouth breathing, dento-facial deformities, orthodontic or speech and language treatment. The procedures were: oral myofunctional and speech evaluation, dentistry evaluation and the appliance of two questionnaires to the children's parents about the child's history and nutrition habits regarding the food consistence. RESULTS: children without tooth crowding usually eat mainly solid food, while those with a crowding arch usually eat softened food, mostly influenced by the habit of drinking while the food is still in the mouth. CONCLUSION: it seems that tooth crowding is related to food consistence. The soften food consistence seems to be an etiological factor or to contribute to tooth crowding. Food consistence as well as tooth crowding seems not to interfere in speech production.