Transmission of yellow fever vaccine virus through blood transfusion and organ transplantation in the USA in 2021: report of an investigation.

BACKGROUND: In 2021, four patients who had received solid organ transplants in the USA developed encephalitis beginning 2-6 weeks after transplantation from a common organ donor. We describe an investigation into the cause of encephalitis in these patients. METHODS: From Nov 7, 2021, to Feb 24, 2022, we conducted a public health investigation involving 15 agencies and medical centres in the USA. We tested various specimens (blood, cerebrospinal fluid, intraocular fluid, serum, and tissues) from the organ donor and recipients by serology, RT-PCR, immunohistochemistry, metagenomic next-generation sequencing, and host gene expression, and conducted a traceback of blood transfusions received by the organ donor. FINDINGS: We identified one read from yellow fever virus in cerebrospinal fluid from the recipient of a kidney using metagenomic next-generation sequencing. Recent infection with yellow fever virus was confirmed in all four organ recipients by identification of yellow fever virus RNA consistent with the 17D vaccine strain in brain tissue from one recipient and seroconversion after transplantation in three recipients. Two patients recovered and two patients had no neurological recovery and died. 3 days before organ procurement, the organ donor received a blood transfusion from a donor who had received a yellow fever vaccine 6 days before blood donation. INTERPRETATION: This investigation substantiates the use of metagenomic next-generation sequencing for the broad-based detection of rare or unexpected pathogens. Health-care workers providing vaccinations should inform patients of the need to defer blood donation for at least 2 weeks after receiving a yellow fever vaccine. Despite mitigation strategies and safety interventions, a low risk of transfusion-transmitted infections remains. FUNDING: US Centers for Disease Control and Prevention (CDC), the Biomedical Advanced Research and Development Authority, and the CDC Epidemiology and Laboratory Capacity Cooperative Agreement for Infectious Diseases.

Rheumatoid meningitis sine arthritis.

Rheumatoid meningitis is a rare and very serious extra-articular manifestation of rheumatoid arthritis. We present a case of a 7()year-old female with no history of arthritis who developed stroke-like symptoms, seizures, psychosis and compulsive behavior. Serial brain magnetic resonance images (MRI) over four months demonstrated progressive interhemispheric meningeal thickening. She had mild lymphocytic pleocytosis on the cerebrospinal fluid analysis and serum anti-cyclic citrullinated peptide antibodies resulted positive in high titers. She underwent a brain biopsy showing necrotizing granulomas consistent with rheumatoid meningitis. Her symptoms resolved with treatment with glucocorticoids and cyclophosphamide. She has not been diagnosed with rheumatoid arthritis even after 1 year of follow up. Clinicians should be aware of the possibility of rheumatoid meningitis without rheumatoid arthritis and keep it on the differential for patients with aseptic meningitis and otherwise negative work up.

Elevated potassium provides an ionic mechanism for deep brain stimulation in the hemiparkinsonian rat.

The mechanism of high-frequency stimulation used in deep brain stimulation (DBS) for Parkinson's disease (PD) has not been completely elucidated. Previously, high-frequency stimulation of the rat entopeduncular nucleus, a basal ganglia output nucleus, elicited an increase in [K(+)](e) to 18 mm, in vitro. In this study, we assessed whether elevated K(+) can elicit DBS-like therapeutic effects in hemiparkinsonian rats by employing the limb-use asymmetry test and the self-adjusting stepping test. We then identified how these effects were meditated with in-vivo and in-vitro electrophysiology. Forelimb akinesia improved in hemiparkinsonian rats undergoing both tests after 20 mm KCl injection into the substantia nigra pars reticulata (SNr) or the subthalamic nucleus. In the SNr, neuronal spiking activity decreased from 38.2 ± 1.2 to 14.6 ± 1.6 Hz and attenuated SNr beta-frequency (12-30 Hz) oscillations after K(+) treatment. These oscillations are commonly associated with akinesia/bradykinesia in patients with PD and animal models of PD. Pressure ejection of 20 mm KCl onto SNr neurons in vitro caused a depolarisation block and sustained quiescence of SNr activity. In conclusion, our data showed that elevated K(+) injection into the hemiparkinsonian rat SNr improved forelimb akinesia, which coincided with a decrease in SNr neuronal spiking activity and desynchronised activity in SNr beta frequency, and subsequently an overall increase in ventral medial thalamic neuronal activity. Moreover, these findings also suggest that elevated K(+) may provide an ionic mechanism that can contribute to the therapeutic effects of DBS for the motor treatment of advanced PD.

The immunological challenges of cell transplantation for the treatment of Parkinson's disease.

Dopaminergic cell transplantation is an experimental therapy for Parkinson's disease (PD). It has many potential theoretical advantages over current treatment strategies such as providing continuous local dopaminergic replenishment, eliminating motor fluctuations and medication-induced dyskinesias, slowing down disease progression or even reversing disease pathology in the host. Recent studies also show that dopaminergic cell transplants provide long-term neuromodulation in the basal ganglia that simulates the combined effects of oral dopaminergic therapy and surgical therapies like deep brain stimulation, the contemporary therapeutic approach to advanced PD. However, dopaminergic cell transplantation in PD as not been optimized and current experimental techniques have many drawbacks. In published experiments to date of attempted dopaminergic grafting in PD, the major challenges are unacceptable graft-induced dyskinesias or failure of such grafts to exceed the benefits afforded by sham surgery. A deleterious host immune response to the transplant has been implicated as a major putative cause for these adverse outcomes. This article focuses on recent advances in understanding the immunology of the transplantation in PD and possible methods to overcome adverse events such that we could translate cell replacement strategies into viable clinical treatments in the future.

The effect of striatal dopaminergic grafts on the neuronal activity in the substantia nigra pars reticulata and subthalamic nucleus in hemiparkinsonian rats.

The electrophysiological correlates of parkinsonism in the basal ganglia have been well studied in patients with Parkinson's disease and animal models. Separately, striatal dopaminergic cell transplantation has shown promise in ameliorating parkinsonian motor symptoms. However, the effect of dopaminergic grafts on basal ganglia electrophysiology has not thoroughly been investigated. In this study, we transplanted murine foetal ventral mesencephalic cells into rats rendered hemiparkinsonian by 6-hydroxydopamine injection. Three months after transplantation, extracellular and local field potential recordings were taken under urethane anaesthesia from the substantia nigra pars reticulata and subthalamic nucleus along with cortical electroencephalograms and were compared to recordings from normal and hemiparkinsonian controls. Recordings from cortical slow-wave activity and global activation states were analysed separately. Rats with histologically confirmed xenografts showed behavioural improvement measured by counting apomorphine-induced rotations and with the extended body axis test. Firing rates in both nuclei were not significantly different between control and grafted groups. However, burst firing patterns in both nuclei in the slow-wave activity state were significantly reduced (P < 0.05) in rats with large surviving grafts, compared to hemiparkinsonian controls. The neuronal firing entropies and oscillations in both nuclei were restored to normal levels in the large-graft group. Electroencephalogram spike-triggered averages also showed normalization in the slow-wave activity state (P < 0.05). These results suggest that local continuous dopaminergic stimulation exerts a normalizing effect on the downstream parkinsonian basal ganglia firing patterns. This novel finding is relevant to future preclinical and clinical investigations of cell transplantation and the development of next-generation therapies for Parkinson's disease that ameliorate pathophysiological neural activity and provide optimal recovery of function.