Human Neural Progenitors Expressing GDNF Enhance Retinal Protection in a Rodent Model of Retinal Degeneration.

Stem cell therapy for retinal degenerative diseases has been extensively tested in preclinical and clinical studies. However, preclinical studies performed in animal models at the early stage of disease do not optimally translate to patients that present to the clinic at a later stage of disease. As the retina degenerates, inflammation and oxidative stress increase and trophic factor support declines. Testing stem cell therapies in animal models at a clinically relevant stage is critical for translation to the clinic. Human neural progenitor cells (hNPC) and hNPC engineered to stably express GDNF (hNPCGDNF) were subretinally injected into the Royal College of Surgeon (RCS) rats, a well-established model for retinal degeneration, at early and later stages of the disease. hNPCGDNF treatment at the early stage of retinal degeneration provided enhanced visual function compared to hNPC alone. Treatment with both cell types resulted in preserved retinal morphology compared to controls. hNPCGDNF treatment led to significantly broader photoreceptor protection than hNPC treatment at both early and later times of intervention. The phagocytic role of hNPC appears to support RPE cell functions and the secreted GDNF offers neuroprotection and enables the extended survival of photoreceptor cells in transplanted animal eyes. Donor cells in the RCS rat retina survived with only limited proliferation, and hNPCGDNF produced GDNF in vivo. Cell treatment led to significant changes in various pathways related to cell survival, antioxidative stress, phagocytosis, and autophagy. A combined stem cell and trophic factor therapy holds great promise for treating retinal degenerative diseases including retinitis pigmentosa and age-related macular degeneration.

Emotional- and cognitive-like responses induced by social defeat stress in male mice are modulated by the BNST, amygdala, and hippocampus.

Introduction: Chronic exposure to social defeat stress (SDS) has been used to investigate the neurobiology of depressive- and anxiety-like responses and mnemonic processes. We hypothesized that these affective, emotional, and cognitive consequences induced by SDS are regulated via glutamatergic neurons located in the bed nucleus of the stria terminalis (BNST), amygdaloid complex, and hippocampus in mice. Methods: Here, we investigated the influence of chronic SDS on (i) the avoidance behavior assessed in the social interaction test, (ii) the anxiety-like behavior (e.g., elevated plus-maze, and open field tests) (iii) depressive-like behaviors (e.g., coat state, sucrose splash, nesting building, and novel object exploration tests), (iv) the short-term memory (object recognition test), (v) ΔFosB, CaMKII as well as ΔFosB + CaMKII labeling in neurons located in the BNST, amygdaloid complex, dorsal (dHPC) and the ventral (vHPC) hippocampus. Results: The main results showed that the exposure of mice to SDS (a) increased defensive and anxiety-like behaviors and led to memory impairment without eliciting clear depressive-like or anhedonic effects; (b) increased ΔFosB + CaMKII labeling in BNST and amygdala, suggesting that both areas are strongly involved in the modulation of this type of stress; and produced opposite effects on neuronal activation in the vHPC and dHPC, i.e., increasing and decreasing, respectively, ΔFosB labeling. The effects of SDS on the hippocampus suggest that the vHPC is likely related to the increase of defensive- and anxiety-related behaviors, whereas the dHPC seems to modulate the memory impairment. Discussion: Present findings add to a growing body of evidence indicating the involvement of glutamatergic neurotransmission in the circuits that modulate emotional and cognitive consequences induced by social defeat stress.

Human iPSC-derived neural progenitor cells secreting GDNF provide protection in rodent models of ALS and retinal degeneration.

Human induced pluripotent stem cells (iPSCs) are a renewable cell source that can be differentiated into neural progenitor cells (iNPCs) and transduced with glial cell line-derived neurotrophic factor (iNPC-GDNFs). The goal of the current study is to characterize iNPC-GDNFs and test their therapeutic potential and safety. Single-nuclei RNA-seq show iNPC-GDNFs express NPC markers. iNPC-GDNFs delivered into the subretinal space of the Royal College of Surgeons rodent model of retinal degeneration preserve photoreceptors and visual function. Additionally, iNPC-GDNF transplants in the spinal cord of SOD1G93A amyotrophic lateral sclerosis (ALS) rats preserve motor neurons. Finally, iNPC-GDNF transplants in the spinal cord of athymic nude rats survive and produce GDNF for 9 months, with no signs of tumor formation or continual cell proliferation. iNPC-GDNFs survive long-term, are safe, and provide neuroprotection in models of both retinal degeneration and ALS, indicating their potential as a combined cell and gene therapy for various neurodegenerative diseases.

Down Regulation of Catsper1 Expression by Calmodulin Inhibitor (Calmidazolium): Possible Implications for Fertility.

The CatSper channel localizes exclusively in the flagella of sperm cells. The Catsper1 protein, together with three pore units, is essential for the CatSper Channel formation, which produces flagellum hyperactivation and confers sperm fertility. Catsper1 expression is dependent on Sox transcription factors, which can recognize in vitro at least three Sox binding sites on the promoter. Sox transcription factors have calmodulin-binding domains for nuclear importation. Calmodulin (CaM) is affected by the specific inhibitor calmidazolium (CMZ), which prevents the nuclear transport of Sox factors. In this work, we assess the regulation of the Catsper1 promoter in vivo by Sox factors in the murine testis and evaluate the effects of the inhibitor calmidazolium on the expression of the Casper genes, and the motility and fertility of the sperm. Catsper1 promoter has significant transcriptional activity in vivo; on the contrary, three Sox site mutants in the Catsper1 promoter reduced transcriptional activity in the testis. CaM inhibition affects Sox factor nuclear transport and has notable implications in the expression and production of Catsper1, as well as in the motility and fertility capability of sperm. The molecular mechanism described here might conform to the basis of a male contraceptive strategy acting at the transcriptional level by affecting the production of the CatSper channel, a fundamental piece of male fertility.

Linfadenitis tuberculosa en niños: Revisión sistemática de reportes de caso

Objetivo: Realizar una revisión sistemática de casos de linfadenitis tuberculosa en niños publicados en la literatura hasta abril de 2022. Materiales y Métodos: Se buscó reportes de casos de linfadenitis tuberculosa por M. tuberculosis en niños, en las bases de datos de Scopus, PubMed, Science Direct, Web of Science, LILACs, Ovid MEDLINE, EBSCO y BMJ Case Reports. Resultados: Se seleccionó 41 reportes, que informaron 46 pacientes. La mayoría fueron varones (52,2%), de 8,5 (5-12) años, con tiempo de enfermedad de 2 (1-5) meses. Las manifestaciones clínicas más frecuentes fueron linfadenopatía palpable (60,9%), fiebre (52,2%) y tos (26,1%). También se encontró pérdida de peso (17,4%), escrófula (15,2%), dificultad respiratoria (13%), hiporexia (13%), dolor localizado (13%), exantema cutáneo (13%), sudoración nocturna (4,3%), dolor abdominal (4,3%) e ictericia (2,2%). Los ganglios cervicales fueron los más comprometidos (71,4%). Solo 17,4% tuvo compromiso pulmonar asociado. El PPD fue positivo en 77,1%, la baciloscopia en 17,2%, la histopatología en 94,1% y el cultivo en 58,8%. Conclusiones: La linfadenitis tuberculosa en niños fue más frecuente en varones, entre 5 y 12 años, inmunizados por BCG y sin contacto conocido de tuberculosis. Los síntomas más frecuentes fueron linfadenopatía palpable, fiebre y tos. Además, se presentaron cuadros atípicos con dificultad respiratoria, dolor localizado, exantema cutáneo, dolor abdominal e ictericia. Los ganglios cervicales fueron los más afectados. El estudio histopatológico fue la prueba con mayor sensibilidad diagnóstica detectando el 94,1% de casos.

Objective: To conduct a systematic review of tuberculous lymphadenitis cases in children published until April 2022. Materials and methods: Case reports of tuberculous lymphadenitis by M. tuberculosis in children were searched in Scopus, PubMed, Science Direct, Web of Science, LILACs, Ovid MEDLINE, EBSCO, and BMC Case Reports databases. Results: Forty-one reports were selected and a total of 46 patients were included. The majority were males (52,2%) of 8,5 (5-12) years old. The time of disease was 2 (1-5) months. The most frequent clinical manifestations were palpable lymphadenopathy (60,9%), fever (52,2%) and cough (26,1%). Weight loss (17,4%), scrofula (15,2%), respiratory distress (13%), hyporexia (13%), localized pain (13%), skin rash (13%), night sweats (4.3%), abdominal pain (4.3%) and jaundice (2,2%) were also founded. Cervical nodes were most frequently involved (71,4%). Only 17,4% were associated with lung involvement. PPD was positive in 77.1%, bacilloscopy in 17.2%, histopathology in 94,1% and culture in 58,8%. Conclusions: Tuberculous lymphadenitis in children was more frequent in boys, between 5 and 12 years, immunized by BCG and without known contact with tuberculosis. The principal symptoms were palpable lymphadenopathy, fever and cough. However, atypical symptoms were respiratory difficulty, localized pain, skin rash, abdominal pain, and jaundice. Cervical nodes were the most affected. The test with greatest sensitivity was the histopathological study which detected 94,1% of cases.

Carcinoide atípico de timo en varón de 39 años: Reporte de caso / Atypical carcinoid of thymus in a 39-year-old-man: A case report

RESUMEN El carcinoide atípico (CA) de timo es la neoplasia más agresiva y rara que surge en el mediastino anterior y que pertenece a los tumores primarios neuroendocrinos de timo. La mayoría de los pacientes son asintomáticos y según la extensión de la enfermedad pueden presentar desde tos, disnea, dolor torácico hasta síndrome de vena cava superior. Esta presentación clínica inespecífica disminuye la probabilidad del diagnóstico temprano que, sumado con el estadio avanzado al debut y la imposibilidad de resección quirúrgica reduce la tasa de supervivencia. El objetivo es dar a conocer la presentación clínica, imagenológica y patológica en un varón de 39 años con CA de timo cuyo diagnóstico definitivo se basó en el estudio histopatológico (morfología carcinoide, mitosis 0-1/2 mm2, necrosis, Ki 67 = 12%) y marcadores inmunofenotípicos del tumor (CD 56 (+), Panqueratina (+), Sinaptofisina (+), TTF -1 (-)).

ABSTRACT The atypical carcinoid (AC) of thymus is the most aggressive and uncommon neoplasm in the anterior mediastinum, that belongs to the neuroendocrine primary tumors of thymus. Most patients are asymptomatic and according to the disease extension they may present with cough, dyspnea, chest pain, and superior cava vein syndrome. This non-specific clinical presentation reduces the likelihood for making an early diagnosis; and this, together with disease stage and lack of surgical resection reduces the survival rate. The aim of this paper is to describe the clinical presentation in a 39-year old male with thymus carcinoid whose diagnosis was based on histopathological studies (carcinoid morphology, 0-1/2 mitoses/mm2), necrosis, Ki67, 12%), and immunophenotypic tumor markers (CD56(+), Pankeratin (+), Synaptophysin (+), and TTF-1 (-)).