Zika virus as a new pathogenic agent within the Toxoplasma gondii, Rubella virus, Cytomegalovirus, and Herpes simplex (TORCH) virus family: where do we stand?

Viral infections in low-income countries such as Brazil pose a significant challenge for medical authorities, with epidemics such as Zika virus infection having lasting effects. The increase in microcephaly among newborns has prompted investigations into the association between Zika virus and this congenital syndrome. The severity and prevalence of microcephaly led to the declaration of national and international emergencies. Extensive research has been conducted to understand the teratogenic effects of Zika virus, particularly its impact on neural progenitor cells in the fetal brain. Various pre- and postnatal imaging techniques, such as ultrasound, magnetic resonance imaging (MRI), and postnatal computed tomography (CT), have played crucial roles in diagnosing and monitoring malformations linked to congenital Zika virus infection in the central nervous system (CNS). These modalities can detect brain parenchymal abnormalities, calcifications, cerebral atrophy, and callosal anomalies. Additionally, three-dimensional ultrasound and fetal MRI provide detailed anatomical images, while CT can identify calcifications that are not easily detected by other methods. Despite advancements in imaging, there are still unanswered questions and ongoing challenges in comprehending the long-term effects and developmental impairments in children affected by Zika virus. Radiologists continue to play a crucial role in diagnosing and assisting in the management of these cases.

The contribution of decentralized water systems on water quality in Maniema province, DRC.

Decentralized water systems (DWS) distribute water in remote African areas. Throughout an intervention in Maniema, Congo, the influence of a DWS performing chlorination in the community's water quality was measured. Additionally, a socio-economic and WASH practices survey was conducted in the communities. Free residual chlorine (FRC) and microbiological contamination were measured; at the borehole, treatment site, distribution points, and households's water containers. In Big Five, water was collected from unimproved sources before DWS construction. Despite that, only 16,6% of households used efficient water treatment methods, resulting in 73% of water stored unsafe for consumption. After construction, household water quality drastically improved, regardless of FRC fluctuations; 93% of samples were classified as low health risk (safe). The renovation guaranteed continuous supply through electro-chlorinators in RVA, where chlorination was intermittent. Water from DWS with adequate chlorine levels prevented microbiological contamination in households for 12 hours. Although economically attractive, the system's sustainability will require future evaluation.

Effects of transcranial direct current stimulation on visuospatial attention in air traffic controllers.

Visuospatial attention is a cognitive skill essential to the performance of air traffic control activities. We evaluated the effect of an anodic session of transcranial low-intensity direct current stimulation (tDCS) right parietal associated with cognitive training of visuospatial attention of 21 air traffic controllers. Within-subject designs were used, with all volunteers undergoing two tDCS sessions; an experimental (2 mA anodic) and control (sham) performed concomitantly with the cognitive training (2-Back). Visuospatial performance was measured using the Attention Network Test for Interactions and Vigilance pre- and post-intervention. The results indicate that after an active parietal tDCS session, the ATCOs showed faster responses, but not more accurate, for visuospatial attention in its aspects of orientation and reorientation. This result was significant when comparing baseline and post-tests in the active tDCS group. Comparing the post-tests between the tDCS active and sham groups, it is possible to infer a trend of improvement in the results based on faster and more accurate responses, which suggests a possible refinement of the ATCO's attentional orientation. However, this population may eventually have reached a plateau in the performance of this skill. From the analysis of the results we arrive at the following hypotheses: (I) the increase in cortical excitability mediated by anodic tDCS frequently recorded may not be accompanied by improvements in behavioural measures; (II) the interaction between anodic tDCS with another event of increased excitability-execution of a cognitive task, may have hindered the occurrence of neuroplasticity; (III) the air traffic control activity may be associated with a high level of attention, which may have contributed to a ceiling effect for the development of this skill; (IV) online assessments may be more relevant to identify acute effects; (V) repeated sessions may be more efficient to find cumulative effects; (VI) the analysis of interactions between attentional networks can contribute to the study of visuospatial attention; (VII) tDCS protocols aimed at ATCO need to consider the specifics of this audience, such as circadian rhythm and sleep and fatigue conditions.

Rab35 controls cilium length, function and membrane composition.

Rab and Arl guanine nucleotide-binding (G) proteins regulate trafficking pathways essential for the formation, function and composition of primary cilia, which are sensory devices associated with Sonic hedgehog (Shh) signalling and ciliopathies. Here, using mammalian cells and zebrafish, we uncover ciliary functions for Rab35, a multitasking G protein with endocytic recycling, actin remodelling and cytokinesis roles. Rab35 loss via siRNAs, morpholinos or knockout reduces cilium length in mammalian cells and the zebrafish left-right organiser (Kupffer's vesicle) and causes motile cilia-associated left-right asymmetry defects. Consistent with these observations, GFP-Rab35 localises to cilia, as do GEF (DENND1B) and GAP (TBC1D10A) Rab35 regulators, which also regulate ciliary length and Rab35 ciliary localisation. Mammalian Rab35 also controls the ciliary membrane levels of Shh signalling regulators, promoting ciliary targeting of Smoothened, limiting ciliary accumulation of Arl13b and the inositol polyphosphate 5-phosphatase (INPP5E). Rab35 additionally regulates ciliary PI(4,5)P2 levels and interacts with Arl13b. Together, our findings demonstrate roles for Rab35 in regulating cilium length, function and membrane composition and implicate Rab35 in pathways controlling the ciliary levels of Shh signal regulators.

Venolymphatic malformations: prenatal diagnosis using magnetic resonance imaging, perinatal outcomes and long-term follow-up.

BACKGROUND: Venolymphatic malformations are benign. Fetal MRI can more precisely demonstrate an infiltrative pattern of malformations than US. OBJECTIVE: To evaluate perinatal outcomes and long-term follow-up of fetal venolymphatic malformations treated in different medical facilities using fetal MRI. MATERIALS AND METHODS: This retrospective cohort study evaluated 20 pregnant women between 22 weeks and 37 weeks of gestation who were referred from different institutions. They presented with fetuses with various diagnoses of cystic masses on routine US. The cases were studied using MRI. We analyzed prenatal data, perinatal outcomes and long-term follow-up. RESULTS: We reviewed the MRI scans of 20 patients with venolymphatic malformation. Referral diagnosis was changed in 40% (8/20) of cases, with postnatal concordance of 100% (20/20). Moreover, 65% (13/20) presented with venolymphatic malformation in more than one body segment. The neck was affected in 70% (14/20) of fetuses, while the head and thorax were affected in 30% (6/20) and 45% (9/20), respectively. There were intrathoracic lesions in 35% (7/20), lesions in the abdomen in 30% (6/20), and lesions in the perineum and extremities in 10% (2/20) each. Tracheal displacement, neck deflection and anatomical displacement caused by tumoral compression were present in 15% (3/20) of cases. Moreover, 25% (5/20) of newborns required neonatal intensive care unit admission, and all presented with cervical or thoracic venolymphatic malformation. Furthermore, 50% (10/20) of cases presented with complete resolution after medical therapy. The intrathoracic and cervical residuals (35%, 7/20) were monitored and treated. CONCLUSION: MRI showed good correlation with postnatal examination of venolymphatic malformation, was useful in the differential diagnosis of fetal cysts on US, and presented a significant postnatal correlation with thoracic infiltration. The outcomes of prenatally diagnosed venolymphatic malformations are good despite the varying protocols among medical facilities.

Central Nervous System Effects of Intrauterine Zika Virus Infection: A Pictorial Review.

Relatively few agents have been associated with congenital infections involving the brain. One such agent is the Zika virus, which has caused several outbreaks worldwide and has spread in the Americas since 2015. The Zika virus is an arbovirus transmitted by infected female mosquito vectors, such as the Aedes aegypti mosquito. This virus has been commonly associated with congenital infections of the central nervous system and has greatly increased the rates of microcephaly. Ultrasonography (US) remains the method of choice for fetal evaluation of congenital Zika virus infection. For improved assessment of the extent of the lesions, US should be complemented by magnetic resonance (MR) imaging. Postnatal computed tomography and MR imaging can also unveil additional findings of central nervous system involvement, such as microcephaly with malformation of cortical development, ventriculomegaly, and multifocal calcifications in the cortical-subcortical junction, along with associated cortical atrophy. The calcifications may be punctate, dystrophic, linear, or coarse and may follow a predominantly bandlike distribution. A small anterior fontanelle with prematurely closed sutures is also observed with Zika virus infection. In this review, the prenatal and postnatal neurologic imaging findings of congenital Zika virus infection are covered. Radiologists must be aware of this challenging entity and have knowledge of the various patterns that may be depicted with each imaging modality and the main differential diagnosis of the disease. As in other neurologic infections, serial imaging is able to help demonstrate the progression of the findings. ©RSNA, 2017.

Prenatal Diagnosis of Caroli Disease Associated With Autosomal Recessive Polycystic Kidney Disease by 3-D Ultrasound and Magnetic Resonance Imaging.

BACKGROUND: Caroli disease is a very rare congenital anomaly characterized by non-obstructive saccular or fusiform dilatation of the intrahepatic bile ducts. It is associated with bile stagnation and hepatolithiasis, which explain the recurrent cholangitis and portal hypertension as a consequence of congenital liver fibrosis. Although there are several reports of diagnosis in childhood and adult life, the prenatal diagnosis using conventional 2-D ultrasound is rare, with few reports in the literature. CASE: We present a case of a 26-year-old primigravid woman at 24 weeks of gestation which 3-D ultrasound in the rendering mode clearly revealed the enlarged fetal kidneys and the increased abdominal volume, confirming the diagnosis of autosomal recessive polycystic kidney disease. The MRI was essential to the prenatal diagnosis of Caroli disease, identifying the congenital saccular dilations of intrahepatic bile ducts.

Clinical and epidemiological profiles from a case series of 26 Brazilian CADASIL patients.

BACKGROUND: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a genetic cause of ischemic stroke and the most common form of non-atherosclerotic stroke. Despite being the most prevalent vascular hereditary disease, clinical data regarding the Brazilian population are scarce. Considering that the Brazilian population has one of the most heterogeneous genetic constitutions in the world, knowledge about genetic and epidemiological profiles is mandatory. The present study aimed to elucidate the epidemiological and clinical features of CADASIL in Brazil. METHODS: We performed a case series study comprising 6 rehabilitation hospitals in Brazil and reported the clinical and epidemiological data from the medical records of patients admitted from 2002 to 2019 with genetic confirmation. RESULTS: We enrolled 26 (16 female) patients in whom mutations in exons 4 and 19 were the most common. The mean age at the onset of the disease was of 45 years. Ischemic stroke was the first cardinal symptom in 19 patients. Cognitive impairment, dementia, and psychiatric manifestations were detected in 17, 6, and 16 patients respectively. In total, 8 patients had recurrent migraines, with aura in 6 (75%) of them. White matter hyperintensities in the temporal lobe and the external capsule were found in 20 (91%) and 15 patients (68%) respectively. The median Fazekas score was of 2. Lacunar infarcts, microbleeds, and larger hemorrhages were observed in 18 (82%), 9, and 2 patients respectively. CONCLUSION: The present is the most extensive series of Brazilian CADASIL patients published to date, and we have reported the first case of microbleeds in the spinal cord of a CADASIL patient. Most of our clinical and epidemiological data are in accordance with European cohorts, except for microbleeds and hemorrhagic strokes, for which rates fall in between those of European and Asian cohorts.

ANTECEDENTES: Arteriopatia cerebral autossômica dominante com enfartes subcorticais e leucoencefalopatia (Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy, CADASIL, em inglês) é uma causa genética de acidente vascular cerebral (AVC) isquêmico e a forma mais comum de acidente vascular cerebral não aterosclerótico. Apesar de ser a doença vascular hereditária mais prevalente que há, os dados clínicos para a população brasileira são escassos. Considerando que o Brasil tem uma das constituições genéticas mais heterogêneas do mundo, o conhecimento sobre perfis genéticos e epidemiológicos é obrigatório. Este estudo teve como objetivo elucidar as características clínicas e epidemiológicas de pacientes com CADASIL no Brasil. MéTODOS: Apresentamos uma série de casos envolvendo 6 hospitais de reabilitação no Brasil, e relatamos dados clínicos e epidemiológicos de prontuários de pacientes admitidos entre 2002 e 2019 com confirmação genética. RESULTADOS: incluímos 26 pacientes (16 mulheres) em que as mutações nos éxons 4 e 19 eram as mais comuns. A idade média de início da doença foi de 45 anos. O AVC isquêmico foi o primeiro sintoma cardinal em 19 pacientes. Comprometimento cognitivo, demência e manifestações psiquiátricas foram detectados em 17, seis e 16 pacientes, respectivamente. Ao todo, 8 pacientes apresentavam enxaqueca, sendo com aura em 6 (75%) pacientes. Hiperintensidades de substância branca no polo temporal e na cápsula externa foram encontradas em 20 (91%) e 15 pacientes (68%), respectivamente. A pontuação mediana na escala de Fazekas foi de 2. Infartos lacunares, microssangramentos e macro-hemorragias foram observadas em 18 (82%), 9 (41%) e 2 (9%) pacientes, respectivamente. CONCLUSãO: O presente estudo representa a mais extensa série de pacientes brasileiros com CADASIL publicada até o momento, e relatamos o primeiro caso de micro-hemorragia na medula espinhal de um paciente com CADASIL. A maior parte dos nossos dados clínicos e epidemiológicos está de acordo com as coortes europeias, exceto para micro-hemorragias e macro-hemorragias, para as quais as taxas se enquadram entre as das coortes europeias e asiáticas.

A Brazilian multicentre study on the clinical and epidemiological profiles of 1116 patients with amyotrophic lateral sclerosis and its phenotypic variants.

Objective: We conducted a multicentre, cross-sectional analysis of Brazilian patients with amyotrophic lateral sclerosis (ALS) and its phenotypic variants. We describe and compare their clinical and epidemiological data. Methods: We collected data from 1,116 patients who visited seven rehabilitation hospitals in the SARAH network from 1 January 2009 to 20 March 2020. This representative sample of patients was from 308 cities in 25 states from the country's five regions. Results: The median age at onset was 55 years, and we found a significant linear correlation between the age at onset and the Municipal Human Development Index (MHDI) but not survival time. We found a four-year difference using a cutoff value of 0.750 (p < 0.001). There was a male predominance, with a 1.2:1 sex ratio. The median time from onset to diagnosis was 17.6 months, and the most common phenotypic presentations were spinal-onset and bulbar-onset ALS (62.7% and 14.7%, respectively). In total, 12.9% of the patients had familial ALS, likely due to the overrepresentation of ALS type 8 patients in our population. Conclusions: In general, our numbers are consistent with most international series and with those of other Brazilian cohorts. When patients were analyzed according to their MHDI a considerable delay in symptom onset was found, suggesting the possibility of an environmental effect on these patients. Brazil has a longer diagnostic delay which is similar to other less-developed countries. This is a substantial concern and should be a priority for health authorities and neurology societies.

A retrospective cohort study of 238,000 COVID-19 hospitalizations and deaths in Brazil.

The coronavirus disease (COVID-19) pandemic has overwhelmed health care systems in many countries and bed availability has become a concern. In this context, the present study aimed to analyze the hospitalization and intensive care unit (ICU) times in patients diagnosed with COVID-19. The study covered 55,563 ICU admissions and 238,075 hospitalizations in Brazilian Health System units from February 22, 2020, to June 7, 2021. All the patients had a positive COVID-19 diagnosis. The symptoms analyzed included: fever, dyspnea, low oxygen saturation (SpO2 < 95%), cough, respiratory distress, fatigue, sore throat, diarrhea, vomiting, loss of taste, loss of smell, and abdominal pain. We performed Cox regression in two models (ICU and hospitalization times). Hazard ratios (HRs) and survival curves were calculated by age group. The average stay was 14.4 days for hospitalized patients and 12.4 days for ICU patients. For hospitalized cases, the highest hazard mean values, with a positive correlation, were for symptoms of dyspnea (HR = 1.249; 95% confidence interval [CI], 1.225-1.273) and low oxygen saturation (HR = 1.157; 95% CI 1.137-1.178). In the ICU, the highest hazard mean values were for respiratory discomfort (HR = 1.194; 95% CI 1.161-1.227) and abdominal pain (HR = 1.100; 95% CI 1.047-1.156). Survival decreased by an average of 2.27% per day for hospitalization and 3.27% per day for ICU stay. Survival by age group curves indicated that younger patients were more resistant to prolonged hospital stay than older patients. Hospitalization was also lower in younger patients. The mortality rate was higher in males than females. Symptoms related to the respiratory tract were associated with longer hospital stay. This is the first study carried out with a sample of 238,000 COVID-19 positive participants, covering the main symptoms and evaluating the hospitalization and ICU times.

Concern About Falling, Confidence in Balance, Quality of Life, and Depression Symptoms in Community-Dwelling Older Adults After a 24-week Dual-Task Training With Variable and Fixed Priority: A Randomized Controlled Trial.

OBJECTIVE: To evaluate the effect of a 24-week dual-task training with progression from variable to fixed priority on the concern about falling, confidence in balance, quality of life, and depression symptoms in community-dwelling older adults. METHODS: A total of 60 participants (60-80 y.o.) were randomly allocated into a dual-task training group with progression from variable to fixed priority (experimental group) or into a dual-task training group with variable priority (control group). RESULTS: No between-group difference was observed after the intervention. A significant time effect showed a reduction in concern about falling [mean difference (MD) = -2.91)] and depression symptoms (MD = -1.66), an increase in the physical function (MD = 7.86), overall mental health (MD = 5.82), perception of vitality, energy, and less fatigue (MD = 10.45), general perception of overall health (MD = 6.81), and their health compared to the last year (MD = 11.89). CONCLUSION: The experimental protocol was not superior to the control one. However, both protocols improved these outcomes.

Head Lice at School: Traditional Medicine and Community Engagement.

Purpose: The prevalence of head lice in poor rural communities and urban slums is estimated to be between 28% and 43% in Brazil, respectively. Children are among the most affected, often in clusters within schools. We launched a program intending to tackle the social stigma associated with head lice using scientific information and a local traditional remedy as a way to lower the prevalence of head lice in a low-resource community. Methods: A program involving the entire school community and the teachers addressed how to treat head lice and avoid new infestations. An affordable solution widely used in traditional Brazilian medicine was provided for the ones infested. Evaluation of the outcome was based on direct observation and was designed as a satisfaction survey. The study complied with the criteria for Standards for Reporting Qualitative Research (SRQR). Results: Two hundred and eighty participants, including parents and siblings of the school children, took part in the program. Among them, 24% (N=67) had head lice, with girls representing 85% of cases; 74.7% of participants infested with head lice were between 4 and 10 years old; 55.2% (N=37) of participants infested showed no signs of nits or adult lice after the program. Conclusions: This experience suggests that the use of playful activities associated with a well-known and accessible local product to treat head lice in low-income families gathered a high degree of community adherence and may be an important tool in overcoming health inequalities.

Physalis angulata concentrated ethanolic extract suppresses nociception and inflammation by modulating cytokines and prostanoids pathways.

Physalins are seco-steroids with a variety of pharmacological activities already described. In this study the pharmacological properties of a standardized concentrated ethanolic extract from Physalis angulata (CEEPA), rich in physalins B, D, F and G, were studied in models of pain and inflammation in mice. Inflammatory mediators were measured by radioimmunoassay and Real-Time PCR in mice paws after the CFA stimuli. Systemic administration of CEEPA produced antinociceptive effect on the writhing test and formalin test. In the writhing test, physalins B, D, F and G showed that the antinociceptive effect of CEEPA is more potent than that of these purified compounds. In addition, CEEPA reduced the levels of TNF-α, IL-1ß, COX-2 and iNOS mRNA in the CFA-induced paw inflammation. Likewise, CEEPA decreased the TNF-α, IL-1ß and PGE2 paw levels. In conclusion, CEEPA induces antinociceptive and anti-inflammatory effects, with improved pharmacological potency relative to pure physalins, associated to modulation of cytokine and cyclooxygenase pathways.

Hypertension treatment with Combretum micranthum or Hibiscus sabdariffa, as decoction or tablet: a randomized clinical trial.

Hibiscus sabdariffa L. (local names: bissap, karkade) and Combretum micranthum (kinkeliba) are widely known in traditional medicines and popular beliefs for their antihypertensive effect. This study assessed the clinical effectiveness of these two plants in the galenic forms of tablet and brew (decoction) in noncomplicated hypertensive patients. In total, 219 hypertensive patients with systolic blood pressure (SBP) between 140 and 180 mmHg and/or diastolic blood pressure (DBP) between 90 and 110 mmHg, without cardiovascular or renal complications, were involved in a multicentric randomized clinical trial in Senegal comparing five treatment regimens: bissap tablets (2 × 375 mg/day), bissap brew (10 g of calyx/day), kinkeliba tablets (2 × 200 mg/day), kinkeliba brew (10 g of leaves/day), and captopril (2 × 50 mg/day) as control. During the 6 months' follow-up, a significant and equivalent decrease of SBP was observed with the herbal drug approach (-19.5 ± 16.1 mmHg, p < 0.001) and control group (-19.7 ± 16.7, p < 0.001). Regarding the galenic forms, the brews tended to be slightly more effective than tablets (reduction of SBP: -20.7 ± 15.1 mmHg vs -18.7 ± 16.7). The rates of clinically significant effectiveness (decrease in SBP ≥ 10 mmHg) were 75%, 67%, and 65% with bissap, kinkeliba, and captopril, respectively. After 6 months, target blood pressure of <140/90 mmHg was attained by 49% of patients with bissap, 51% with kinkeliba and 40% with captopril. Bissap and kinkeliba appeared, at doses utilized, to be as effective as captopril over the 6 months' follow-up. In subsequent studies, brews might be started with a lower dosage.

Hibiscus sabdariffa, a Treatment for Uncontrolled Hypertension. Pilot Comparative Intervention.

In Iraq, in 2019, there were about 1.4 million Internally Displaced Persons (IDP); medical treatments were often interrupted. The feasibility of using Hibiscus sabdariffa (HS) decoction to curb hypertension was evaluated. A multicentric comparative pilot intervention for 121 participants with high blood pressure (BP) (≥140/90 mmHg) was conducted. Participants of the intervention group (with or without conventional medication) received HS decoction on a dose regimen starting from 10 grams per day. BP was measured five times over six weeks. The major active substances were chemically quantified. Results: After 6 weeks, 61.8% of participants from the intervention group (n = 76) reached the target BP < 140/90 mmHg, compared to 6.7% in the control group (n = 45). In the intervention group, a mean (±SD) reduction of 23.1 (±11.8) mmHg and 12.0 (±11.2) for systolic and diastolic BP, respectively, was observed, while in the control group the reduction was 4.4 (±10.2)/3.6 (±8.7). The chemical analysis of the starting dose indicated a content of 36 mg of total anthocyanins and 2.13 g of hibiscus acid. The study shows the feasibility of using HS decoction in IDP's problematic framework, as hibiscus is a safe, local, affordable, and culturally accepted food product.

Preventing nosocomial infections in resource-limited settings: An interventional approach in healthcare facilities in Burkina Faso.

BACKGROUND: Nosocomial pathogens are transmitted by contamination of surfaces causing healthcare-associated infections (HAI). The impact of locally produced disinfectant with operational training as a means to improve hygiene in resource-limited healthcare facilities and prevent HAI was evaluated. METHOD: In Burkina Faso, 4 types of electro-chlorinator devices that convert salt and water into sodium hypochlorite through electrolysis were installed in 26 healthcare facilities distributed across 3 sanitary districts. The program was evaluated at 4 months and 11 months and performance compared with a control group. RESULTS: After 11 months, over 90% of the facilities applied 8 of the 11 essential hygiene practices defined by the Ministry of Health, compared to 20% in the control group. 61.5% of the healthcare facilities improved the chlorine concentration of their sodium hypochlorite solutions, reaching an average concentration of 5.1 g/L compared to an average of 2.1 g/L in the control group. Additionally, a cost-benefit analysis demonstrated that locally produced sodium hypochlorite led to daily savings ranging between 2.7 and 53 euros depending on the device compared with the purchase of chlorine tablets. CONCLUSION: Results, therefore, suggest that electro-chlorinator devices in addition to hygiene sensitization can be a simple, cost-effective and tailored intervention to reduce the prevalence of HAI in low-resource settings.

Neuronal megalin mediates synaptic plasticity-a novel mechanism underlying intellectual disabilities in megalin gene pathologies.

Donnai-Barrow syndrome, a genetic disorder associated to LRP2 (low-density lipoprotein receptor 2/megalin) mutations, is characterized by unexplained neurological symptoms and intellectual deficits. Megalin is a multifunctional endocytic clearance cell-surface receptor, mostly described in epithelial cells. This receptor is also expressed in the CNS, mainly in neurons, being involved in neurite outgrowth and neuroprotective mechanisms. Yet, the mechanisms involved in the regulation of megalin in the CNS are poorly understood. Using transthyretin knockout mice, a megalin ligand, we found that transthyretin positively regulates neuronal megalin levels in different CNS areas, particularly in the hippocampus. Transthyretin is even able to rescue megalin downregulation in transthyretin knockout hippocampal neuronal cultures, in a positive feedback mechanism via megalin. Importantly, transthyretin activates a regulated intracellular proteolysis mechanism of neuronal megalin, producing an intracellular domain, which is translocated to the nucleus, unveiling megalin C-terminal as a potential transcription factor, able to regulate gene expression. We unveil that neuronal megalin reduction affects physiological neuronal activity, leading to decreased neurite number, length and branching, and increasing neuronal susceptibility to a toxic insult. Finally, we unravel a new unexpected role of megalin in synaptic plasticity, by promoting the formation and maturation of dendritic spines, and contributing for the establishment of active synapses, both in in vitro and in vivo hippocampal neurons. Moreover, these structural and synaptic roles of megalin impact on learning and memory mechanisms, since megalin heterozygous mice show hippocampal-related memory and learning deficits in several behaviour tests. Altogether, we unveil a complete novel role of megalin in the physiological neuronal activity, mainly in synaptic plasticity with impact in learning and memory. Importantly, we contribute to disclose the molecular mechanisms underlying the cognitive and intellectual disabilities related to megalin gene pathologies.