Changes In CNS Research Articles

Metabolic acidosis and sudden infant death syndrome: overlooked data provides insight into SIDS pathogenesis.

Decades of mainstream SIDS research based on the Triple Risk Model and neuropathological findings have failed to provide convincing evidence for a primary CNS-based mechanism behind putative secondary dyshomeostasis (respiratory or cardiac) or impaired arousal. Newly revealed data indicate that severe metabolic acidosis (and severe hyperkalemia) is a common accompaniment in SIDS. This supports the direct effect of sepsis on vital-organ function and occurrence of secondary CNS changes accompanied by the dyshomeostasis leading to SIDS. Using PubMed and Google Scholar literature searches, this paper examines how metabolic acidosis and sepsis might contribute to the underlying pathophysiologic mechanisms in SIDS. The discovery of a series of non-peer-reviewed publications provided the basis for a serious examination of the role of metabolic acidosis and sepsis in SIDS. Most SIDS risk factors relate directly or indirectly to infection. This consequently elevated the position of septic or superantigenic shock and viremia in causing secondary organ failure leading to SIDS. The latter could include diaphragmatic failure, as evidenced by peripheral respiratory (muscle) arrests in experimental septic shock, as well as infectious myositis and diaphragm myopathy in sudden unexpected deaths, including SIDS. In addition, just as acidosis lowers the threshold for ventricular fibrillation and sudden cardiac arrest, it could also contribute to similarly unstable diaphragm excitation states leading to respiratory failure. This paper uniquely reveals compelling evidence for a connection between metabolic acidosis, sepsis, viral infections, and sudden unexpected child deaths and provides a solid basis for further work to define which pathway (or pathways) lead to the tragedy of SIDS. It is recommended that all autopsies in sudden unexpected deaths should include pH, bicarbonate, lactate, and electrolyte measurements, as well as diaphragm histology.

Short-term meditation training alters brain activity and sympathetic responses at rest, but not during meditation

Although more people are engaging in meditation practices that require specialized training, few studies address the issues associated with nervous activity pattern changes brought about by such training. For beginners, it remains unclear how much practice is needed before objective physiological changes can be detected, whether or not they are similar across the novices and what are the optimal strategies to track these changes. To clarify these questions we recruited individuals with no prior meditation experience. The experimental group underwent an eight-week Taoist meditation course administered by a professional, while the control group listened to audiobooks. Both groups participated in audio-guided, 34-min long meditation sessions before and after the 8-week long intervention. Their EEG, photoplethysmogram, respiration, and skin conductance were recorded during the mediation and resting state periods. Compared to the control group, the experimental group exhibited band-specific topically organized changes of the resting state brain activity and heart rate variability associated with sympathetic system activation. Importantly, no significant changes were found during the meditation process prior and post the 8-week training in either of the groups. The absence of notable changes in CNS and ANS activity indicators during meditation sessions, for both the experimental and control groups, casts doubt on the effectiveness of wearable biofeedback devices in meditation practice. This finding redirects focus to the importance of monitoring resting state activity to evaluate progress in beginner meditators. Also, 16 h of training is not enough for forming individual objectively different strategies manifested during the meditation sessions. Our results contributed to the development of tools to objectively monitor the progress in novice meditators and the choice of the relevant monitoring strategies. According to our findings, in order to track early changes brought about by the meditation practice it is preferable to monitor brain activity outside the actual meditation sessions.

Cardiopulmonary testing in long COVID-19 versus non–COVID-19 patients with undifferentiated Dyspnea on exertion

BackgroundDyspnea and fatigue are characteristics of long SARS-CoV-2 (COVID)-19. Cardiopulmonary exercise testing (CPET) can be used to better evaluate such patients. Research questionHow significantly and by what mechanisms is exercise capacity impaired in patients with long COVID who are coming to a specialized clinic for evaluation? Study design and methodsWe performed a cohort study using the Mayo Clinic exercise testing database. Subjects included consecutive long COVID patients without prior history of heart or lung disease sent from the Post-COVID Care Clinic for CPET. They were compared to a historical group of non–COVID patients with undifferentiated dyspnea also without known cardiac or pulmonary disease. Statistical comparisons were performed by t-test or Pearson's chi2 test controlling for age, sex, and beta blocker use where appropriate. ResultsWe found 77 patients with long COVID and 766 control patients. Long COVID patients were younger (47 ± 15 vs 50 ± 10 years, P < .01) and more likely female (70% vs 58%, P < .01). The most prominent difference on CPETs was lower percent predicted peak V̇O2 (73 ± 18 vs 85 ± 23%, p < .0001). Autonomic abnormalities (resting tachycardia, CNS changes, low systolic blood pressure) were seen during CPET more commonly in long COVID patients (34 vs 23%, P < .04), while mild pulmonary abnormalities (mild desaturation, limited breathing reserve, elevated V̇E/V̇CO2) during CPET were similar (19% in both groups) with only 1 long COVID patient showing severe impairment. InterpretationWe identified severe exercise limitation among long COVID patients. Young women may be at higher risk for these complications. Though mild pulmonary and autonomic impairment were common in long COVID patients, marked limitations were uncommon. We hope our observations help to untangle the physiologic abnormalities responsible for the symptomatology of long COVID.

Lactoferrin averts neurological and behavioral impairments of thioacetamide-induced hepatic encephalopathy in rats via modulating HGMB1/TLR-4/MyD88/Nrf2 pathway

Hepatic encephalopathy (HE) is a life-threatening disease caused by acute or chronic liver failure manifested by aberrant CNS changes. In the present study, we aimed to explore the neuroprotective effect of lactoferrin (LF) against thioacetamide (TAA)-induced HE in rats. Animals were divided into four groups, control, LF control, TAA-induced HE, and LF treatment, where LF was administered (300 mg/kg, p.o.) for 15 days in groups 2 and 4 meanwhile, TAA (200 mg/kg, i.p.) was given as two injections on days 13 and 15 for the 3rd and 4th groups. Pretreatment with LF significantly improved liver function observed as a marked decline in serum AST, ALT, and ammonia, together with lowering brain ammonia and enhancing motor coordination as well as cognitive performance. Restoration of brain oxidative status was also noted in the LF-treated group, where lipid peroxidation was hampered, and antioxidant parameters, Nrf2, HO-1, and GSH, were increased. Additionally, LF downregulated HMGB1, TLR-4, MyD88, and NF-κB signaling pathways, together with reducing inflammatory cytokine, TNF-α, and enhancing brain BDNF levels. Moreover, the histopathology of brain and liver tissues revealed that LF alleviated TAA-induced liver and brain deficits. In conclusion, the promising results of LF in attenuating HMGB1/TLR-4/MyD88 signaling highlight its neuroprotective role against HE associated with acute liver injury via ameliorating neuroinflammation, oxidative stress, and stimulating neurogenesis.

EEG changes as an indication of central nervous system involvement following cyclopentolate 1% eye drops; a randomized placebo-controlled pilot study in a pediatric population

ABSTRACT To compare EEG-patterns after instillation of cyclopentolate versus placebo eye drops. Prospective, randomized, placebo-controlled, and observational pilot study is presented. Ophthalmology outpatient clinic Dutch metropolitan hospital. Healthy 6- to 15-year-old volunteers with normal or low BMI requiring a cycloplegic refraction/retinoscopy. Randomized; 1 visit 2 drops cyclopentolate-1% and 1 visit 2 drops placebo (saline-0.9%). Single-blind: conducting researcher. Double blind: subjects, parents, clinical-neurophysiology staff, neurologist, and statistician. A 10-min baseline EEG-recording, drop-application, and follow-up to at least 45 min. Primary outcome: Detection of CNS changes, i.e. EEG-pattern changes, following two drops of cyclopentolate-1%. Secondary outcome: Determination of the extent of these pattern changes. Thirty-six cyclopentolate-1% saline-0.9% EEG registrations were made in 33 subjects; 18 males and 15 females. Three subjects were tested twice (interval 7 months). Nine out of fourteen (64%) of the 11- to 15-year-old children reported impaired memory, attention, alertness, as well as mind wandering following cyclopentolate. Drowsiness and sleep were seen in EEG-recordings of 11 subjects (33%) following cyclopentolate. We observed no drowsiness nor sleep during placebo recordings. The mean time to drowsiness was 23 min. Nine subjects arrived in stage-3 sleep but none arrived in REM-sleep. In subjects without sleep (N=24), significant changes compared to placebo-EEG were present for many leads and parameters. The main findings during awake eye-open recording were as follows: 1) a significant increase of temporal Beta-1,2 and 3-power, and 2) a significant decrease in: a) the parietal and occipital Alpha-2-power, b) the frontal Delta-1-power, c) the frontal total power, and d) the occipital and parietal activation synchrony index. The former finding reflects cyclopentolate uptake in the CNS, and the latter findings provide evidence for CNS suppression. Cyclopentolate-1% eye drops can affect the CNS and may cause altered consciousness, drowsiness, and sleep with concomitant EEG results in both young children and children in puberty. There is evidence that cyclopentolate has the potency to act as a short acting CNS depressant. Nevertheless, however, cyclopentolate-1% can safely be used in children and young adolescents.

Review of Experimental Models of Schizophrenia

Schizophrenia is a severe psychiatric disease that has a lifetime prevalence of 1% in most of the populations studied. The neuropathology and psychopathology of Schizophrenia are still poorly understood. This is attributed to the paucity of adequate animal models. Schizophrenia is a disorder of the human brain. Consequently, the potency of animal models in Schizophrenia research is limited to certain aspects of the disease. One of the most difficult aspects of modelling Schizophrenia in animals has been the lack of a clear and explicit conceptual framework for this disorder. This review discussed drug-induced animal models of Schizophrenia such as Ketamine (NMDA receptor antagonist), Phencyclidine (NMDA receptor antagonist) etc. It also discussed genetic animal models of Schizophrenia which include but not limited to Schizophrenia susceptibility Genes, Neuregulin-1(NRG1), DAT gene, Zinc finger DHH-type3 containing 8 (ZDHHC8) and Dysbindin. It went further to discuss fetal models Schizophrenia, postweaning social isolation and ended with In-Vitro animal models. The use of animal models to improve understanding of the neurochemical and structural CNS changes that precipitate development of Schizophrenia, rather than a focus on treating the symptoms, is a prerequisite to enable new more effective therapeutic strategies to be developed. Because of the complexity and ambiguity of gene-gene and gene-environment interactions in the aetiology of schizophrenia, the challenge of developing more reliable predictive animal models of this disorder, most likely through multiple early-life interventions, is still ongoing.

Differential transcriptomic changes in the central nervous system and urinary bladders of mice infected with a coronavirus.

Multiple sclerosis (MS) often leads to the development of neurogenic lower urinary tract symptoms (LUTS). We previously characterized neurogenic bladder dysfunction in a mouse model of MS induced by a coronavirus, mouse hepatitis virus (MHV). The aim of the study was to identify genes and pathways linking neuroinflammation in the central nervous system with urinary bladder (UB) dysfunction to enhance our understanding of the mechanisms underlying LUTS in demyelinating diseases. Adult C57BL/6 male mice (N = 12) received either an intracranial injection of MHV (coronavirus-induced encephalomyelitis, CIE group), or sterile saline (control group). Spinal cord (SC) and urinary bladders (UB) were collected from CIE mice at 1 wk and 4 wks, followed by RNA isolation and NanoString nCounter Neuroinflammation assay. Transcriptome analysis of SC identified a significantly changed expression of >150 genes in CIE mice known to regulate astrocyte, microglia and oligodendrocyte functions, neuroinflammation and immune responses. Two genes were significantly upregulated (Ttr and Ms4a4a), and two were downregulated (Asb2 and Myct1) only in the UB of CIE mice. Siglec1 and Zbp1 were the only genes significantly upregulated in both tissues, suggesting a common transcriptomic link between neuroinflammation in the CNS and neurogenic changes in the UB of CIE mice.

Silence of resident microglia in GPI anchorless prion disease and activation of microglia in Gerstmann-Sträussler-Scheinker disease and sporadic Creutzfeldt-Jakob disease.

GPI anchorless prion diseases (GPIALPs) show numerous coarse prion protein (PrP) deposits in the CNS but neuropil spongiform changes are mild and the incidence of dementia is low. Here, we examined differences in resident microglial phenotypes between GPIALP (D178fs25) and the other prion diseases Gerstmann-Sträussler-Scheinker (GSS) disease and sporadic Creutzfeldt-Jakob disease (sCJD) with respect to homeostasis and activation. Immunohistochemistry was performed on 2 GPIALP (D178fs25), 4 GSS (P102L), and 4 sCJD cases. Homeostatic microglia expressing TMEM119 and P2RY12 were preserved in GPIALP compared to GSS and sCJD. Microglia/macrophage activation in GSS and sCJD was associated with the extent of spongiform change. Immunoelectron microscopy revealed TMEM119 and P2RY12 in PrP plaque cores. Activated microglia/macrophages expressing HLA-DR and CD68 were predominant in GSS and sCJD whereas in GPIALP, homeostatic microglia were retained and activated microglia/macrophages were rarely observed. These data suggest that PrP deposition in GPIALP is less toxic and that microglia may be immune-tolerant to PrP deposition. This may be associated with milder tissue damage and a low incidence of dementia. Whereas microglia/macrophage activation is considered to be a reaction to tissue injury, this study shows that the degree of microglia/macrophage activity might influence the extent of tissue damage.

ODP261 Non-Ketotic Hyperosmolar Hyperglycemia Induced Hemichorea-Dystonia Syndrome, Without Radiologic Striatopathy

Abstract Background Movement disorder is an uncommon complication of Hyperglycemic crisis. It is often associated with diabetic striatopathy which is a clinico-radiologic entity that is associated with acute changes of the contralateral basal ganglia. Isolated dyskinetic-dystonic disorder without obvious radiologic lesion is a rare clinical entity. Case Report A 42-years-old woman with a history of type 2 diabetes mellitus was admitted with a 1-week history of involuntary right arm and face movements and 3 weeks of polyuria. She had recurrent choreiform right arm movements without athetosis or hemiballismus lasting about 2. Additionally, she experiences right cervicofacial dystonia. There was no involvement of the lower extremities, no loss of consciousness and no other neurologic deficit between attacks. Physical examination was essentially unveiling with no focal neurologic deficits or tremors. Initial work up showed elevated; blood glucose to 620mg/dl (65–110), serum sodium of 148mEq/L (135–145) and serum osmolality of 330mmol/kg (275–295). Work up was negative for acidosis, with pH of 7.39 (7.32–7.42), bicarbonate of 23mEq/L (23–31) and no ketones on urinalysis. Other relevant test including serum bilirubin, transaminases, ammonia level, calcium, ceruloplasmin and cupper were normal. An initial non-contrast CT scan of the brain was negative for acute pathology and MRI did not show any lesions in basal ganglia. E. E. G was also normal. Movements recurred twice in hospital, and she received IV lorazepam without much response. She was diagnosed with non-Ketotic hyperosmolar hyperglycemic chorea- dystonia syndrome. She received IV normal saline and started on insulin therapy resulting in improvement in serum glucose to 255 by the next morning. She was discharge after 72 hours with no recurrence at 2 weeks follow up visit. Discussion Hyperglycemic crisis may rarely be associated with dyskinetic syndromes, often due to the development of diabetic striatopathy and about 80% are without ketosis. The mechanism is believed to be due to impaired GABA synthesis in the basal ganglia. Prevalence of hyperglycemia induced striatopathy stands at 1 per 100,000. The commonest manifestation is that of hemiballismus and chorea. Very few cases of dystonia have been reported. It is a clinico-radiologic diagnosis with basal ganglia abnormalities on imaging stemming from edema, microhemorrhages or calcific changes. There are very few case reports of hyperglycemic dyskinetic syndromes without CNS changes on MRI. The average time for resolution of MRI changes is 60 days thus we believe our patient had no radiologic striatopathy. In majority of cases, resolution of hyperglycemia leads to clinical resolution of dyskinetic spells. Occasionally, some patients may require medications such as antipsychotics including haloperidol, or benzodiazepines such as clonazepam to control movements. In conclusion, movement disorder related to hyperglycemia though rare, can be disabling. Prognosis is excellent if a timely clinical diagnosis is made. Presentation: No date and time listed

Comprehensive study of health effects of plasma technology occupational environment: Exposure to high frequency and intensity noise and toxic gases

ObjectivesTo evaluate on animal models the health effects of the combined or separate exposure to main chemical and physical hazards of plasma-based material processing technology environment. Materials and methodsMale Wistar rats were exposed to actual levels of hazardous factors in plasma technology occupational environment: i.e., ozone and nitrogen oxides (O3 and NOx) in respective concentrations of 0.5 mg/m3 and 1.0 mg/m3 and high-frequency (1000–1600 Hz) of 112 dB intensity noise for 3 h/day, 5 days/week for 12 weeks, with a recovery period of 1 month. ResultsExposure to noise or its combination with chemical factors (ozone, nitrogen oxides) causes non-specific CNS changes testifying for significant excitation dominance, especially in the case of joint exposure. Histological examination of rats’ brain in experimental revealed a pronounced increase in blood filling of small vessels on the tenth day of the experiment, with subsequent intensification of vascular alterations and eventually to cerebral edema. The exposure to noise significantly reduced total thymus, bone marrow and spleen cell numbers and these was also more pronounced under the joint impact of noise and toxic gases. Thymus, but not bone marrow or spleen, mitotic activity was as well reduced under the same modes of exposure. Cytological investigation of film preparations of subcutaneous connective tissue revealed that joint exposure led to microcirculatory disorders, increased number of dark mast cells and reduced degranulation processes indicative of increased autoregulatory processes effective at microvasculature level. ConclusionsHigh-frequency and intensity noise is main stressor factor that has negative impact on CNS and immune system, morphology and functioning of hematopoietic organs (spleen, bone marrow, thymus) and connective tissue. Its negative impact is significantly potentiated by concurrent exposure to ozone and nitrogen oxide, while exposure only to these toxic gases has no significant effect on the above targets.

Auditory processing disorder in elderly

Objectives With an increase in age, peripheral hearing loss and CNS changes occur both structurally and functionally. These changes affect the processes of hearing and listening and auditory data processing. The elderly subjects with normal or near normal auditory sensitivity experience degrees of age-related auditory processing disorder. This study aimed to explore these changes in the elderly population and to compare them with young subjects. Methods In the present study, the dichotic digits test (DDT) was performed to evaluate the binaural auditory processing, and the gap in noise (GIN) detection test was performed to assess the auditory temporal processing function. Results A significant difference was found in the mean approximate threshold and percent of correct answers of GIN between the old and young subjects (p < 0.05). There was also a significant difference in the mean score of DDT in each ear between the two groups (p < 0.05). Conclusion The results showed that binaural auditory processing and auditory temporal processing capabilities reduce in the elderly. Early detection of these changes in the elderly and the design of appropriate rehabilitation programs can markedly improve the performance of elderly people.

Cardiomyocyte‐specific deletion of sarcoglycan‐δ leads to dilated cardiomyopathy, autonomic dysfunction, and exaggerated stress‐induced cardiovascular reactivity

Deficiency of sarcoglycan‐δ (Sgcd) induces disruption of the dystrophin glycoprotein complex, resulting in loss of membrane stability. We have reported that angiotensin II (AngII)‐mediated autonomic dysfunction precedes and predicts development of dilated cardiomyopathy (DCM) in the global Sgcd‐deficient mice [Exp Physiol 2015].The relative contribution of cardiomyocyte‐targeted Sgcd on DCM and autonomic dysfunction remains unknown. Our goal is to determine whether cardiac remodeling in the Sgcd mutations is an intrinsic process of the cardiomyocytes. We have also observed that global Sgcd‐deficient mice with DCM exhibit anxiety‐like behaviors. AngII via type 1 receptors (AT1R) is well‐known to mediate anxiety‐related behaviors, while Ang‐(1‐7) via Mas receptors is anxiolytic. Thus, we hypothesize that Sgcd in the ventricular myocytes is essential for the progression of DCM, and to elicit emotional stress responses. Cardiac‐specific Sgcd‐deficient (cSgcd‐KO) and littermate control (WT) mice were generated by breeding male αMHCcre+(αmyosin‐heavy chain Myh6 promoter drives expression of the cre‐recombinase) withfemaleglobal Sgcd‐deficientmice. Absence of Sgcdin the cardiomyocytes was confirmed by immunohistochemistry and qPCR in the cSgcd‐KO mice. WT (n=11) and cSgcd‐KO (n=14) mice were echoed every month, from 8 weeks of age, to monitor progression of DCM. At ~35 weeks of age, telemeters (DSI) were implanted to measure changes in blood pressure (BP), heart rate (HR) and locomotor activity during acute emotional stress challenge (20 min exposure to predator odor). Autonomic indices including baroreflex sensitivity (BRS, sequence technique), and resting cardiac vagal and sympathetic tone (HR responses to atropine and propranolol, respectively) were calculated. At 36±1 weeks of age, cSgcd‐KO mice exhibit 62% increase in left ventricular (LV) end‐diastolic volume, 58% decrease in LV ejection fraction, and increased cardiac fibrosis (p&lt;0.05 vs. 10 weeks of age). At baseline, cSgcd‐KO mice exhibit lower BP (100±6 vs.121±1 mmHg), reduced BRS (0.72±0.08 vs.2.01±0.05 ms/mmHg) and vagal tone (∆HR= +32±6 vs. +151±18 bpm), and increased sympathetic tone (∆HR= ‐212±12 vs. ‐123±10 bpm) (p&lt;0.05 vs.WT). Paradoxically, given increased basal sympathetic tone and decreased basal vagal tone, stress caused hypotension in the cSgcd‐KO mice with DCM, likely due to reduced cardiac output. This is accompanied by profound increase in AT1R, and reduced expression of Mas and MrgD receptors (ligand for newly identified heptapeptide alamandine) in LV and brainstem (p&lt;0.0001‐0.01 vs. baseline and WT). We conclude ‐ (i) Sgcddeleted exclusively from the cardiac myocytes creates a novel transgenic mouse strain that develops DCM at ~35 weeks of age. (ii) Stress‐evoked profound changes in CNS and systemic hemodynamics occur directly or indirectly, and cannot be ascribed to Sgcd loss in vascular smooth muscle, endothelium, neurons, or astrocytes. (iii) Contributions of the renin‐angiotensin system is pivotal in pathophysiology of Sgcd deficiencies.

CNS imaging characteristics in fibromyalgia patients with and without peripheral nerve involvement

We tested the hypothesis that reduced skin innervation in fibromyalgia syndrome is associated with specific CNS changes. This prospective case–control study included 43 women diagnosed with fibromyalgia syndrome and 40 healthy controls. We further compared the fibromyalgia subgroups with reduced (n = 21) and normal (n = 22) skin innervation. Brains were analysed for cortical volume, for white matter integrity, and for functional connectivity. Compared to controls, cortical thickness was decreased in regions of the frontal, temporal and parietal cortex in the fibromyalgia group as a whole, and decreased in the bilateral pericalcarine cortices in the fibromyalgia subgroup with reduced skin innervation. Diffusion tensor imaging revealed a significant increase in fractional anisotropy in the corona radiata, the corpus callosum, cingulum and fornix in patients with fibromyalgia compared to healthy controls and decreased FA in parts of the internal capsule and thalamic radiation in the subgroup with reduced skin innervation. Using resting-state fMRI, the fibromyalgia group as a whole showed functional hypoconnectivity between the right midfrontal gyrus and the posterior cerebellum and the right crus cerebellum, respectively. The subgroup with reduced skin innervation showed hyperconnectivity between the inferior frontal gyrus, the angular gyrus and the posterior parietal gyrus. Our results suggest that the subgroup of fibromyalgia patients with pronounced pathology in the peripheral nervous system shows alterations in morphology, structural and functional connectivity also at the level of the encephalon. We propose considering these subgroups when conducting clinical trials.

Abstract EP18: Cardiopulmonary Testing In Long Covid Versus Non-CovidPatients With Undifferentiated Dyspnea On Exertion

Background: COVID-19 reveals new manifestations not only in the acute phase but also in the long term. The latter is what has been termed as ‘post acute sequelae of SARS-CoV-2 infection’ (PASC) — or “long COVID”— with dyspnea as one of its hallmarks. Cardiopulmonary stress testing (CPET) is increasingly being used to better evaluate such patients. Objective: To compare CPET findings of long COVID patients versus non-COVID patients with undifferentiated dyspnea on exertion seen at Mayo Clinic. Methods: A cohort study was carried out using Mayo Clinic’s exercise testing database. The study group included 77 PASC patients confirmed by a positive antigen or PCR test with no prior history of heart or lung disease. PASC patients were compared to 766 non-COVID patients with unspecified dyspnea without known diagnosis of cardiac or pulmonary disease. ANOVA according to the general linear model and Pearson’s Chi square were used for the bivariate analysis of the quantitative and categorical variables, respectively. Analyses were controlled for age, sex, and beta blocker use as appropriate. Both HR and SBP at rest and peak exercise were significantly different between groups, although the absolute differences were small. Results: Compared with the control group, the post-COVID patients were younger (mean age 47 SD ±14.9 years versus 50.5 SD ±10.1 years) and more likely to be female (70.1% (54 of 77) vs 57.6% (441 of 766)). Although there were many significant differences in the CPET results, the most outstanding were a lower FAC (73 SD ±19.4% vs 85.2 SD ±20.8%) and peak VO2 (22 SD ±6.4 ml/kg/min vs 25.8 SD ±7.37 ml/kg/min) in the study group (p&lt;.0001). Also, CNS changes during CPET were reported at higher rates (19.5% (15 of 77) vs 11.4% (87 of 766)) while dyspnea at lower rates (55.8% (43 of 77) vs 65.7% (503 of 766)) in post-COVID patients (p=0.02). When adjusting for age and sex, weight was significantly higher in the study group (p=0.03) although the absolute difference was modest and BMI remained not significant. PFTs did not suggest any pulmonary abnormalities. Conclusions: We identified a high rate of severe exercise limitation among long COVID patients. Young women may be at higher risk for these complications. Pre-exercise PFTs and absence of objective respiratory limitation during CPET argue against a primary pulmonary cause of the observed limitations, though evaluation of cardiac, autonomic, and muscular impairment is pending. Further studies are warranted to untangle the physiologic abnormalities responsible for these observations.

EP200: Noonan syndrome associated with focal occipital alopecia in a patient with RAF1 variant: A case report and literature review

Noonan syndrome (NS) is a heterogenous condition characterized by distinctive craniofacial features, cardiac defects, and neurodevelopmental changes and is caused by variants in one of seven genes coding for proteins within the Ras-MAPK pathway. Pathogenic variants in RAF1 account for approximately 3-17% of cases and are associated with a high prevalence of severe hypertrophic cardiomyopathy (HCM) and pulmonary hypertension (PHTN). Cerebrovascular and Chiari I malformations, although rare, have also been described in individuals with RAF-1 NS. To our knowledge, the presence of congenital occipital alopecia in an individual with NS has not been previously reported. We report a patient with a de novo pathogenic heterozygous RAF1 gene sequence variant, c.770C>T (p.Ser257Leu), with atypical scalp findings. Our proband was a 4-week-old female dichorionic, diamniotic twin born at 35 weeks 2 days gestation to nonconsanguineous parents. At birth, her length was 45.7 cm (14th centile), weight was 2656 g (69th centile), and head circumference was 34.5 cm (97th centile). The mother was 38 at the time of birth. There was no history of maternal or gestational diabetes. Prenatal ultrasound was concerning for cystic hygroma. The immediate neonatal course was complicated by acute respiratory failure, left ventricular outflow tract obstruction with concern for coarctation on echocardiogram, poor feeding, and failed newborn hearing screen which prompted transfer to a tertiary NICU for further management. At the time of consultation, the following problems had been identified: bilateral cataracts, significant redundant posterior neck folds that showed fatty soft tissue neck mass without a cystic component, and hypertrophic cardiomyopathy with elevated pulmonary arterial pressures. Physical exam was notable for relative macrocephaly with turricephaly, lowset, posteriorly rotated ears, redundant posterior neck folds, and a focal, 1cm circular area of alopecia at the midline occipital region. These findings were concerning for a RASopathy. Imaging of her superficial midline scalp defect with brain MRI showed a suspected atretic encephalocele, but CT did not reveal any occipital bony defects. After re-evaluation, it was confirmed that there was no intracranial connection or bony defect at the area of the congenital alopecia nor at the level of the suboccipital skin thickening/redundancy. Chromosomal microarray was nondiagnostic and thus exome sequence analysis was preformed which detected the pathogenic RAF1 variant. The diagnosis of RAF1 NS accounts for nearly all of the physical changes seen in our patient, particularly the severe degree of PHTN and HCM, with the exception of her occipital alopecia. Since our initial consultation, the patient continues to grow along NS-specific curve, has persistent mild bilateral hearing loss, and has had interval placement of gastric tube secondary to oral feeding difficulties. There has been mild improvement in cardiac function, septal hypertrophy, and PHTN. She remains seizure-free. This report expands the phenotype of RAF1 Noonan syndrome to include congenital focal alopecia. We recommend that NS should be added to the differential when this same scalp finding is present. Although the presence of this physical finding in our patient was not definitively associated with any underlying structural CNS or bony changes, this case highlights the importance of investigating with detailed cranial and spinal imaging to better characterize cerebral morphology and guide genetic testing in suspected RASopathy cases. Additional cases with this finding are needed to better understand potential associations.

Analysis of Morphological Changes in the CNS and Internal Organs of Macaca mulatta Monkeys after Intracerebral Injection of a Low-Attenuated Rubella Virus Strain.

We studied the localization and severity of morphological changes in CNS and internal organs of animals intacerebrally infected with a low-attenuated rubella virus strain "Orlov-14". The data obtained can be used as morphological criteria reflecting low level of attenuation of rubella virus strains to improve the control of the safety of attenuated strains of live rubella vaccines.

The oral microbiome and inflammation in mild cognitive impairment.

Inflammation and immune mechanisms are believed to play important roles in Alzheimer's disease pathogenesis. Research supports the link between poor oral health and Alzheimer's disease. Periodontal disease and dental caries represent the two most common infections of the oral cavity. This study focused on a precursor to Alzheimer's disease, mild cognitive impairment (MCI). Using 16S rRNA sequencing, we characterized and compared the oral microbiome of 68 older adults who met the criteria for MCI or were cognitively normal, then explored relationships between the oral microbiome, diagnostic markers of MCI, and blood markers of systemic inflammation. Two taxa, Pasteurellacae and Lautropia mirabilis were identified to be differentially abundant in this cohort. Although systemic inflammatory markers did not differentiate the two groups, differences in five cerebrospinal fluid inflammatory mediators were identified and had significant associations with MCI. Because inflammatory markers may reflect CNS changes, pursuing this line of research could provide opportunities for new diagnostic tools and illuminate mechanisms for prevention and mitigation of Alzheimer's disease.

Characterization of Therapeutic Drug Monitoring Practices of Voriconazole and Posaconazole at a Pediatric Hospital.

To characterize the voriconazole and posaconazole serum trough ordering practices in patients receiving prophylactic and treatment antifungal therapy. A retrospective chart review over a 6-year period of pediatric patients who received voriconazole and/or posaconazole for >24 hours. A total of 113 patients were included in this study and of these patients, 105 received voriconazole and 16 received posaconazole during the study period. Additionally, 167 trough levels were assessed in this study. Only 50% and 54% of levels were considered within goal recommendations for voriconazole and posaconazole, respectively. The median dose required to achieve goal trough concentration was dependent on drug, indication, and dosage form. Lastly, the most common adverse drug reactions (ADRs) were hepatoxicity, QTc prolongation, and CNS changes, which were in concordance with ADRs documented in the clinical trials for voriconazole and posaconazole. Approximately 20% of patients receiving either voriconazole or posaconazole died during the study period and the median trough in both groups was subtherapeutic. Increased monitoring of trough concentrations may be warranted to prevent death or breakthrough invasive fungal infections. Further studies are warranted for assessing the relationship between trough concentrations and treatment outcomes as well as relationship between dosing and achieving goal trough concentrations.

Изучение морфологических изменений в ЦНС и внутренних органах обезьян Macaca mulatta при интрацеребральном введении низкоаттенуированного штамма вируса краснухи

Изучение морфологических изменений в ЦНС и внутренних органах обезьян Macaca mulatta при интрацеребральном введении низкоаттенуированного штамма вируса краснухи

Evaluation of acute oral toxicity of a herbomineral supplement for immunity against mastitis

Mastitis, one of the costliest health problems faced by dairy farms, is an inflammation of the mammary gland parenchyma, which, together with physical, chemical and microbiological changes of milk, is characterized by an increase in the number of somatic cells in the milk and by pathological changes in the mammary tissue. AV/IAM/16 is a herbomineral supplement for immunity against mastitis. A study was undertaken to evaluate the acute oral toxicity potential of AV/IAM/16 (M/s Ayurvet Limited, India) according to OECD 423 guidelines. Six (3 male and 3 female) Swiss albino mice were used for the study, where each animal served as its own control. After procurement, the animals were kept in the cages for seven days for acclimatization. Thereafter, the animals were fasted overnight; food but not water was withheld for 3-4 hours. Following the period of fasting, the animals were weighed and the test substance was administered orally. Following the oral administration of the test substance, the animals were observed over a period of 14 days for manifestation of toxic effects and mortality. The observations included changes in skin, coat and eyes; and changes in respiratory, circulatory, CNS, autonomic, somatic activity and behavior. Clinical signs like muscular tremors, convulsions, salivation, diarrhea, lethargy, sleep, and coma, if observed, were recorded. At the end of 14 days, necropsy and histopathological parameters were also studied. No toxic effects or mortalities were observed during the study and, hence, AV/IAM/16 was found to be safe for oral use.