Epstein-Barr virus (EBV) is a human-specific gamma-herpes virus of the Lymphocryptovirus genus that has succeeded to colonize more than 90% of the adult population. EBV’s co-evolution with humans has ...established a largely harmless coexistence that depends on the variability of viral gene expression and on the immunological host response. Though infection with EBV is generally harmless, the virus is associated with multiple human tumors, such as Burkitt lymphoma, classical Hodgkin lymphoma, nasopharyngeal carcinoma, post-transplant lymphoproliferative disorders, and AIDS lymphomas. The role of EBV in the malignant transformation is still enigmatic even after more than 40 years of research on this virus. EBV readily infects B-lymphocytes in vitro. After infection the virus establishes a latent infection and expresses 9 viral proteins. The concerted effect of these EBV proteins will be the activation and proliferation of the infected B cells. This viral gene expression pattern was named type III latency. As the EBV-infected B cells with type III latency are highly immunogenic they are readily detected and killed by the specific cytotoxic T cells. In contrast to the EBV-infected normal B cells, the majority of the EBV-carrying tumors do not express all the nine proteins; rather they express only EBNA-1 or EBNA1 together with the latent membrane proteins (LMP-1 and LMP-2). The factors that determine what viral genes EBV will express in the different normal and malignant cells are only partially known. Motivated by the lack of in vitro models in which to study the interaction of EBV with the malignant Hodgkin/Reed-Sternberg (HRS) cells, we infected with EBV one of the Hodgkin lymphoma-derived cell lines and studied the viral gene expression in this EBV-converted subline. In this system we identified two cytokines, IL-4 and IL-13, that could modulate the viral gene expression (specifically, induce the expression of LMP-1) and with their help we could for the first time reconstitute in vitro the EBV gene expression seen in the classical Hodgkin lymphomas in vivo. We have also studied the molecular mechanisms that are responsible for the induction of LMP-1 by IL-4 and IL13. Through these studies we identified STAT6 as an important inducer of LMP-1 expression. As STAT6 is constitutively activated in the majority of Hodgkin lymphomas, our results not only provides an explanation how LMP-1 is expressed in the EBV-carrying HRS cells, but might also have future therapeutic implications. Further work identified two additional cytokines, IL-10 and IL-21, which could induce the expression of LMP-1 in EBV-positive B cell and NK cell lymphoma-derived cell lines. The effect of IL-21 was pleiotropic: it could induce LMP-1 in cells that did not express it, and it induced the plasma cell differentiation and down-regulation of expression of the EBV nuclear antigens (EBNA-1 to -6) in type III lymphoblastoid and Burkitt lymphoma cell lines. Furthermore, when isolated human CD4+ T cells were co-cultured with different EBVcarrying lymphoma cell lines, we found that upon activation they were capable of inducing the expression of LMP-1, just as the recombinant cytokines did.Altogether our results provide evidence for an important role for the cytokines secreted by CD4+ T or other inflammatory cells in the modulation of EBV latent gene expression.
Balance impairment in Parkinson's disease is multifactorial and its changes due to subthalamic stimulation vary in different studies.
We aimed to analyze the combination of predictive clinical ...factors of balance impairment in patients with Parkinson's disease treated with bilateral subthalamic stimulation for at least one year.
We recruited 24 patients with Parkinson's disease treated with bilateral subthalamic stimulation and 24 healthy controls. They wore an Opal monitor (APDM Inc.) consisting of three-dimensional gyroscopes and accelerometers in the lumbar region. We investigated four stimulation conditions (bilateral stimulation OFF, bilateral stimulation ON, and unilateral right- and left-sided stimulation ON) with four tests: stance on a plain ground with eyes open and closed, stance on a foam platform with eyes open and closed. Age, disease duration, the time elapsed after implantation, levodopa, and stimulation responsiveness were analyzed. The distance of stimulation location from the subthalamic motor center was calculated individually in each plane of the three dimensions. We analyzed the sway values in the four stimulation conditions in the patient group and compared them with the control values. We explored factor combinations (with age as confounder) in the patient group predictive for imbalance with cluster analysis and a machine-learning-based multiple regression method.
Sway combined from the four tasks did not differ in the patients and controls on a group level. The combination of the disease duration, the preoperative levodopa responsiveness, and the stimulation responsiveness predicted individual stimulation-induced static imbalance. The more affected patients had more severe motor symptoms; primarily, the proprioceptive followed by visual sensory feedback loss provoked imbalance in them when switching on the stimulation.
The duration of the disease, the severity of motor symptoms, the levodopa responsiveness, and additional sensory deficits should be carefully considered during preoperative evaluation to predict subthalamic stimulation-induced imbalance in Parkinson's disease.
Abstract Introduction A different innervation pattern of proximal and distal muscles from the contra- and ipsilateral motor circuits raises the question as to whether bilateral, contra- and ...ipsilateral subthalamic stimulation may have different effects on the distal and proximal movements of the upper limb. To answer this question, we performed kinematic analyzes in patients with Parkinson's disease. Methods Twenty-eight Parkinsonian patients treated by bilateral subthalamic stimulation were examined with an age-matched control group of 28 healthy subjects. They performed 14 seconds of finger tapping, hand grasping and pronation-supination. The patient group performed these sessions in four conditions (BOTH ON, BOTH OFF, CONTRA ON, IPSI ON) after withdrawal of dopaminergic medication for 12 hours and a fifth condition after taking medication (BOTH ON-MED ON). A motion sensor with a three-dimensional gyroscope was worn on the index finger. Speed, amplitude, rhythm and decrement of movements were calculated and compared across these conditions. Results Speed and amplitude of the more distal movements were improved similarly by contra- and bilateral stimulation. Bilateral stimulation was more effective than contralateral stimulation for the more proximal movements. Contra- and bilateral stimulation ameliorated the rhythm similarly in each movement task. Decrement of distal and proximal movements was not affected by the stimulation conditions. Conclusion This is the first study to show that the outcome of bi- and unilateral subthalamic stimulation on proximal and distal upper limb movements should be evaluated separately postulating the different somatotopic organization of subloops in the cortico-basal ganglia motor circuits.
Short- and long-term outcomes from endovascular thrombectomy (EVT) for large vessel occlusion stroke remain variable. Numerous relevant predictors have been identified, including severity of ...neurological deficits, age, and imaging features. The latter is typically defined as acute changes (most commonly Alberta Stroke Programme Early CT Score, ASPECTS, at presentation), but there is little information on the impact of imaging assessment of premorbid brain health as a determinant of outcome.
To examine the impact of automated measures of stroke severity and underlying brain frailty on short- and long-term outcomes in acute stroke treated with EVT.
In 215 patients with anterior circulation stroke, who subsequently underwent EVT, automated analysis of presenting non-contrast CT scans was used to determine acute ischemic volume (AIV) and e-ASPECTS as markers of stroke severity, and cerebral atrophy as a marker of brain frailty. Univariate and multivariate logistic regression were used to identify significant predictors of NIHSS improvement, modified Rankin scale (mRS) at 90 and 30 days, mortality at 90 days and symptomatic intracranial hemorrhage (sICH) following successful EVT.
For long-term outcome, atrophy and presenting NIHSS were significant predictors of mRS 0-2 and death at 90 days, whereas age did not reach significance in multivariate analysis. Conversely, for short-term NIHSS improvement, AIV and age were significant predictors, unlike presenting NIHSS. The interaction between age and NIHSS was similar to the interaction of AIV and atrophy for mRS 0-2 at 90 days.
Combinations of automated software-based imaging analysis and clinical data can be useful for predicting short-term neurological outcome and may improve long-term prognostication in EVT. These results provide a basis for future development of predictive tools built into decision-aiding software in stroke.
We investigated the effect of deep brain stimulation on dynamic balance during gait in Parkinson's disease with motion sensor measurements and predicted their values from disease-related factors. We ...recruited twenty patients with Parkinson's disease treated with bilateral subthalamic stimulation for at least 12 months and 24 healthy controls. Six monitors with three-dimensional gyroscopes and accelerometers were placed on the chest, the lumbar region, the two wrists, and the shins. Patients performed the instrumented Timed Up and Go test in stimulation OFF, stimulation ON, and right- and left-sided stimulation ON conditions. Gait parameters and dynamic balance parameters such as double support, peak turn velocity, and the trunk's range of motion and velocity in three dimensions were analyzed. Age, disease duration, the time elapsed after implantation, the Hoehn-Yahr stage before and after the operation, the levodopa, and stimulation responsiveness were reported. We individually calculated the distance values of stimulation locations from the subthalamic motor center in three dimensions. Sway values of static balance were collected. We compared the gait parameters in the OFF and stimulation ON states and controls. With cluster analysis and a machine-learning-based multiple regression method, we explored the predictive clinical factors for each dynamic balance parameter (with age as a confounder). The arm movements improved the most among gait parameters due to stimulation and the horizontal and sagittal trunk movements. Double support did not change after switching on the stimulation on the group level and did not differ from control values. Individual changes in double support and horizontal range of trunk motion due to stimulation could be predicted from the most disease-related factors and the severity of the disease; the latter also from the stimulation-related changes in the static balance parameters. Physiotherapy should focus on double support and horizontal trunk movements when treating patients with subthalamic deep brain stimulation.
•We examined the effect of anterior thalamic nucleus (ANT)-deep brain stimulation (DBS) on heart rate variability (HRV) in patients with drug-resistant epilepsy.•ANT-DBS increased HRV in patients ...irrespective of responder-status, ANT-hit ratio-seemed to influence HRV-changes.•ANT-DBS might positively influence autonomic regulation, additional prospective studies are required to replicate this finding.
Heart rate variability (HRV) changes were investigated by several studies after resective epilepsy surgery/vagus nerve stimulation. We examined anterior thalamic nucleus (ANT)-deep brain stimulation (DBS) effects on HRV parameters.
We retrospectively analyzed 30 drug-resistant epilepsy patients’ medical record data and collected electrocardiographic epochs recorded during video- electroencephalography monitoring sessions while awake and during N1- or N2-stage sleep pre-DBS implantation surgery, post-surgery but pre-stimulation, and after stimulation began.
The mean square root of the mean squared differences between successive RR intervals and RR interval standard deviation values differed significantly (p < 0.05) among time-points, showing increased HRV post-surgery. High (0.15–0.4 Hz) and very low frequency (<0.04 Hz) increased, while low frequency (0.04–0.15 Hz) and the LF/HF ratio while awake decreased, suggesting improved autonomic regulation post-surgery. Change of effect size was larger in patients where both activated contacts were located in the ANT than in those where only one or none of the contacts hit the ANT.
In patients with drug-resistant epilepsy, ANT-DBS might positively influence autonomic regulation, as reflected by increased HRV.
To gain a more comprehensive outcome estimation after DBS implantation, we suggest including HRV measures with seizure count in the post-surgery follow-up protocol.
Data about the coronavirus disease 2019 (COVID-19) pandemic’s collateral damage on ischemic stroke (IS) care during the second epidemic wave in Central Europe are limited. We sought to evaluate the ...impact of the COVID-19 outbreak on Hungarian IS care during the two epidemic waves. This retrospective observational study was based on a nationwide reimbursement database that encompasses all IS admissions and all reperfusion interventions, i.e., intravenous thrombolysis (IVT) and endovascular therapy (EVT) from 2 January 2017 to 31 December 2020 in Hungary. COVID-19 pandemic’s effect on the number of IS admissions and reperfusion interventions were analyzed using different statistics: means, medians, trends, relative rates, and linear relationships. The mean and median values of IS admissions and reperfusion interventions decreased only in some measure during the COVID-periods. However, trend analysis demonstrated a significant decline from the trends. The decline’s dynamic and amplitude have differed for each variable. In contrast to IVT, the number of IS admissions and EVTs negatively correlated with the epidemic waves’ amplitude. Besides, the decrease in the number of IS admissions was more pronounced than the decrease in the number of reperfusion interventions. Our study demonstrated a significant disruption in IS care during the COVID-19 epidemic in Hungary, in which multiple different factors might play a role. The disproportionate reduction of IS admission numbers could partially be explained by the effect of health emergency operative measures and changes in patients’ social behavior. Further studies are needed to evaluate the causes of our observations.
Background Balance impairment in Parkinson’s disease is multifactorial and its changes due to subthalamic stimulation vary in different studies. Objective We aimed to analyze the combination of ...predictive clinical factors of balance impairment in patients with Parkinson’s disease treated with bilateral subthalamic stimulation for at least one year. Methods We recruited 24 patients with Parkinson’s disease treated with bilateral subthalamic stimulation and 24 healthy controls. They wore an Opal monitor (APDM Inc.) consisting of three-dimensional gyroscopes and accelerometers in the lumbar region. We investigated four stimulation conditions (bilateral stimulation OFF, bilateral stimulation ON, and unilateral right- and left-sided stimulation ON) with four tests: stance on a plain ground with eyes open and closed, stance on a foam platform with eyes open and closed. Age, disease duration, the time elapsed after implantation, levodopa, and stimulation responsiveness were analyzed. The distance of stimulation location from the subthalamic motor center was calculated individually in each plane of the three dimensions. We analyzed the sway values in the four stimulation conditions in the patient group and compared them with the control values. We explored factor combinations (with age as confounder) in the patient group predictive for imbalance with cluster analysis and a machine‐learning‐based multiple regression method. Results Sway combined from the four tasks did not differ in the patients and controls on a group level. The combination of the disease duration, the preoperative levodopa responsiveness, and the stimulation responsiveness predicted individual stimulation-induced static imbalance. The more affected patients had more severe motor symptoms; primarily, the proprioceptive followed by visual sensory feedback loss provoked imbalance in them when switching on the stimulation. Conclusions The duration of the disease, the severity of motor symptoms, the levodopa responsiveness, and additional sensory deficits should be carefully considered during preoperative evaluation to predict subthalamic stimulation-induced imbalance in Parkinson’s disease.
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