Human Embryonic Stem Cell-Derived Immature Midbrain Dopaminergic Neurons Transplanted in Parkinsonian Monkeys.

Human embryonic stem cells (hESCs) differentiate into specialized cells, including midbrain dopaminergic neurons (DANs), and Non-human primates (NHPs) injected with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine develop some alterations observed in Parkinson's disease (PD) patients. Here, we obtained well-characterized DANs from hESCs and transplanted them into two parkinsonian monkeys to assess their behavioral and imaging changes. DANs from hESCs expressed dopaminergic markers, generated action potentials, and released dopamine (DA) in vitro. These neurons were transplanted bilaterally into the putamen of parkinsonian NHPs, and using magnetic resonance imaging techniques, we calculated the fractional anisotropy (FA) and mean diffusivity (MD), both employed for the first time for these purposes, to detect in vivo axonal and cellular density changes in the brain. Likewise, positron-emission tomography scans were performed to evaluate grafted DANs. Histological analyses identified grafted DANs, which were quantified stereologically. After grafting, animals showed signs of partially improved motor behavior in some of the HALLWAY motor tasks. Improvement in motor evaluations was inversely correlated with increases in bilateral FA. MD did not correlate with behavior but presented a negative correlation with FA. We also found higher 11C-DTBZ binding in positron-emission tomography scans associated with grafts. Higher DA levels measured by microdialysis after stimulation with a high-potassium solution or amphetamine were present in grafted animals after ten months, which has not been previously reported. Postmortem analysis of NHP brains showed that transplanted DANs survived in the putamen long-term, without developing tumors, in immunosuppressed animals. Although these results need to be confirmed with larger groups of NHPs, our molecular, behavioral, biochemical, and imaging findings support the integration and survival of human DANs in this pre-clinical PD model.

Latent tuberculosis infection (LTBI) in health-care workers: a cross-sectional study at a northern Peruvian hospital.

Background: Healthcare workers (HCWs) have a higher risk of latent tuberculosis infection (LTBI) and active tuberculosis than the general population. In HCWs, the risk of tuberculosis infection depends on the local tuberculosis prevalence, HCWs' characteristics, the healthcare facility, and prevention and control measures. We aimed to estimate the prevalence and risk factors for LTBI in HCWs at a northern Peruvian hospital. Methods: This study had two phases: (1) a cross-sectional phase involving recruitment, history taking, and sampling for the Interferon-Gamma Release Assays (IGRA test), and (2) a prospective follow-up of IGRA-positive participants. We enrolled direct and non-direct patient caregivers among HCWs. We defined an LTBI case if the IGRA test was positive and clinical, laboratory, and radiological evaluations for active tuberculosis were negative. Results: We recruited 308 participants between November 2022 and May 2023. The mean age was 38.6 ± 8.3 years. Over 75% of the participants were female. The most common job category was technicians (30.5%), physicians (22.7%), nurses (20.5%), and other HCWs groups (17.5%). Most participants worked in hospital wards (28.2%), diagnostics departments (16.9%), and critical care departments (15.6%). The LTBI prevalence among HCWs was 17.86% (95% CI 13.84-22.70). In multivariate analysis, after adjusting for age, time working in our hospital, and family history of tuberculosis, males had a higher risk of LTBI (aPR 1.69, 95% CI 1.01-2.77) than females. Working for more than 10 years increased the risk of LBTI (aPR 2.4, 95% CI 1.44-3.97) compared to working for ≤10 years. Even further, participants who had worked for more than 20 years had an aPR of 4.31 (95% CI 1.09-13.65) compared to those with ≤10 years. Similarly, occupational exposure increased the risk of LTBI (aPR 2.21, 95% CI 1.27-4.08) compared to those HCWs not occupationally exposed. Conclusion: The LTBI prevalence in HCWs at a northern Peruvian hospital was lower compared to other Peruvian cities. Males, more experienced, and occupational exposed HCWs are at higher risk of LTBI. LTBI prevalence in Peruvian HCWs is still high. More studies are needed to address some aspects this study has not examined.

Dopaminergic Dependency of Cholinergic Pallidal Neurons.

We employed the whole-cell patch-clamp method and ChAT-Cre mice to study the electrophysiological attributes of cholinergic neurons in the external globus pallidus. Most neurons were inactive, although approximately 20% displayed spontaneous firing, including burst firing. The resting membrane potential, the whole neuron input resistance, the membrane time constant and the total neuron membrane capacitance were also characterized. The current-voltage relationship showed time-independent inward rectification without a "sag". Firing induced by current injections had a brief initial fast adaptation followed by tonic firing with minimal accommodation. Intensity-frequency plots exhibited maximal average firing rates of about 10 Hz. These traits are similar to those of some cholinergic neurons in the basal forebrain. Also, we examined their dopamine sensitivity by acutely blocking dopamine receptors. This action demonstrated that the membrane potential, excitability, and firing pattern of pallidal cholinergic neurons rely on the constitutive activity of dopamine receptors, primarily D2-class receptors. The blockade of these receptors induced a resting membrane potential hyperpolarization, a decrease in firing for the same stimulus, the disappearance of fast adaptation, and the emergence of a depolarization block. This shift in physiological characteristics was evident even when the hyperpolarization was corrected with D.C. current. Neither the currents that generate the action potentials nor those from synaptic inputs were responsible. Instead, our findings suggest, that subthreshold slow ion currents, that require further investigation, are the target of this novel dopaminergic signaling.

Spontaneous Activity of Neuronal Ensembles in Mouse Motor Cortex: Changes after GABAergic Blockade.

The mouse motor cortex exhibits spontaneous activity in the form of temporal sequences of neuronal ensembles in vitro without the need of tissue stimulation. These neuronal ensembles are defined as groups of neurons with a strong correlation between its firing patterns, generating what appears to be a predetermined neural conduction mode that needs study. Each ensemble is commonly accompanied by one or more parvalbumin expressing neurons (PV+) or fast spiking interneurons. Many of these interneurons have functional connections between them, helping to form a circuit configuration similar to a small-world network. However, rich club metrics show that most connected neurons are neurons not expressing parvalbumin, mainly pyramidal neurons (PV-) suggesting feed-forward propagation through pyramidal cells. Ensembles with PV+ neurons are connected to these hubs. When ligand-gated fast GABAergic transmission is blocked, temporal sequences of ensembles collapse into a unique synchronous and recurrent ensemble, showing the need of inhibition for coding cortical spontaneous activity. This new ensemble has a duration and electrophysiological characteristics of brief recurrent interictal epileptiform discharges (IEDs) composed by the coactivity of both PV- and PV+ neurons, demonstrating that GABA transmission impedes its occurrence. Synchronous ensembles are clearly divided into two clusters one of them lasting longer and mainly composed by PV+ neurons. Because an ictal-like event was not recorded after several minutes of IEDs recording, it is inferred that an external stimulus and/or fast GABA transmission are necessary for its appearance, making this preparation ideal to study both the neuronal machinery to encode cortical spontaneous activity and its transformation into brief non-ictal epileptiform discharges.

Clinical Trial Decision Making in Pediatric Sickle Cell Disease: A Qualitative Study of Perceived Benefits and Barriers to Participation.

Clinical trial research forms the foundation for advancing treatments; yet, children with sickle cell disease (SCD) are currently underrepresented. This qualitative study examines decision-making processes of youth with SCD and their caregivers regarding enrollment in clinical trial research. A subsample of participants from a study of clinical trial decision making among youth with health disparity conditions, 23 caregivers and 29 children/teens/young adults with SCD (age, 10 to 29 y), indicated whether or not they would participate in hypothetical medical and psychosocial clinical trials and prioritized barriers and benefits to participation via card sort and semistructured interviews. Audio recordings were transcribed and coded for themes. Participants reported that concerns of potential harm most affected their decision. Secondary factors were potential benefit, manageable study demands, and trust in the medical staff. Caregivers weighed potential harm more heavily than their children. Young children were more likely to endorse potential benefit. Overall, participants stated they would be willing to participate in research if the potential benefit outweighs potential harm and unmanageable study demands. To optimize recruitment, results suggest addressing potential harm first while highlighting potential benefits, creating manageable study demands, and endorsing the future benefits of research to the sickle cell community.

Human metapneumovirus and other respiratory viral infections in children attending a day care center.

Human metapneumovirus (hMPV) is an important cause of acute respiratory infections (ARI). We studied 335 ARI episodes in 74 children<5 years of age attending a day care center during a 1-year period to detect the presence of hMPV and other viruses. Seven (9.5%) children were infected by hMPV and this virus accounted for 2.1% of the ARI episodes.

Encefalocele Frontoetmoideo-nasoorbitario criterios para manejo quirúrgico A propósito de un caso / Frontoethmoid-nasoorbital encephalocele criteria for surgical management About a case

Los meningoencefaloceles son molformaciones congénitas, con una alta incidencia en la selva amazónica ecuatoriana. La variedad fronto-etmoidal es la más común y requiere tratamiento quirúrgico temprano. Los autores combinan un abordaje neuroquirúrgico y craneofacial realizado en un solo tiempo para corregir este tipo de defecto.

Meningoencephaloceles are congenital molformations, with a high incidence in the Ecuadorian Amazon jungle. The fronto-ethmoidal variety is the most common and requires early surgical treatment. The authors combine a neurosurgical and craniofacial approach performed in a single time to correct this type of defect.