Background: The Omicron variant has become the most prevalent SARS-CoV-2 variant. Omicron is known to induce milder lesions compared to the original Wuhan strain. Fatal infection of the Wuhan strain into the brain has been well documented in COVID-19 mouse models and human COVID-19 cases, but apparent infections into the brain by Omicron have not been reported in human adult cases or animal models. In this study, we investigated whether Omicron could spread to the brain using K18-hACE2 mice susceptible to SARS-CoV-2 infection. Results: K18-hACE2 mice were intranasally infected with 1 × 105 PFU of the original Wuhan strain and the Omicron variant of SARS-CoV-2. A follow-up was conducted 7 days post infection. All Wuhan-infected mice showed > 20% body weight loss, defined as the lethal condition, whereas two out of five Omicron-infected mice (40%) lost > 20% body weight. Histopathological analysis based on H&E staining revealed inflammatory responses in the brains of these two Omicron-infected mice. Immunostaining analysis of viral nucleocapsid protein revealed severe infection of neuron cells in the brains of these two Omicron-infected mice. Lymphoid depletion and apoptosis were observed in the spleen of Omicron-infected mice with brain infection. Conclusion Lethal conditions, such as severe body weight loss and encephalopathy, can occur in Omicron-infected K18-hACE2 mice. Our study reports, for the first time, that Omicron can induce brain infection with lymphoid depletion in the mouse COVID-19 model.

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Lysosomal dysfunction is a common pathological feature of neurodegenerative diseases. GTP-binding protein type A1 (GBA1) encodes beta-glucocerebrosidase 1 (GCase 1), a lysosomal hydrolase. Homozygous mutations in GBA1 cause Gaucher disease, the most common lysosomal storage disease, while heterozygous mutations are strong risk factors for Parkinson's disease. However, whether loss of GCase 1 activity is sufficient for lysosomal dysfunction has not been clearly determined. Here, we generated human neuroblastoma cell lines with nonsense mutations in the GBA1 gene using zinc-finger nucleases. Depending on the site of mutation, GCase 1 activity was lost or maintained. The cell line with GCase 1 deficiency showed indications of lysosomal dysfunction, such as accumulation of lysosomal substrates, reduced dextran degradation and accumulation of enlarged vacuolar structures. In contrast, the cell line with C-terminal truncation of GCase 1 but with intact GCase 1 activity showed normal lysosomal function. When alpha-synuclein was overexpressed, accumulation and secretion of insoluble aggregates increased in cells with GCase 1 deficiency but did not change in mutant cells with normal GCase 1 activity. These results demonstrate that loss of GCase 1 activity is sufficient to cause lysosomal dysfunction and accumulation of alpha-synuclein aggregates.
Cell Line ; Enzyme Activation/genetics ; Gene Knockout Techniques ; Gene Order ; Genetic Loci ; Glucosylceramidase/genetics/*metabolism ; Humans ; Lysosomes/*metabolism ; Mutation ; *Protein Aggregation, Pathological/genetics ; Protein Binding ; Zinc Fingers ; alpha-Synuclein/chemistry/*metabolism

Although the role of alpha-synuclein aggregation on Parkinson's disease is relatively well known, the physiological role and the regulatory mechanism governing the expression of alpha-synuclein are unclear yet. We recently reported that alpha-synuclein is expressed and secreted from cultured astrocytes. In this study, we investigated the effect of valproic acid (VPA), which has been suggested to provide neuroprotection by increasing alpha-synuclein in neuron, on alpha-synuclein expression in rat primary astrocytes. VPA concentration-dependently increased the protein expression level of alpha-synuclein in cultured rat primary astrocytes with concomitant increase in mRNA expression level. Likewise, the level of secreted alpha-synuclein was also increased by VPA. VPA increased the phosphorylation of Erk1/2 and JNK and pretreatment of a JNK inhibitor SP600125 prevented the VPA-induced increase in alpha-synuclein. Whether the increased alpha-synuclein in astrocytes is involved in the reported neuroprotective effects of VPA awaits further investigation.
Acetylation ; alpha-Synuclein* ; Animals ; Astrocytes* ; MAP Kinase Signaling System* ; Neurons ; Neuroprotective Agents ; Parkinson Disease ; Phosphorylation ; Rats* ; RNA, Messenger ; Valproic Acid*

The CD4+CD25+ T regulatory cells (Tregs) play an important role in immune tolerance in experimental transplantation but the clinical significance of circulating Tregs in the peripheral blood is undetermined. In 50 kidney transplant (KT) recipients, 29 healthy controls and 32 liver transplant (LT) recipients, the frequency of Tregs was measured with flow cytometry before and after transplantation. In the KT recipients, IL-10 secretion was measured with an enzyme-linked immunospot (ELISPOT) assay. The median frequency of circulating Tregs before KT was similar to that in healthy controls but significantly lower than that in LT patients before transplantation. The frequency of Tregs was significantly decreased in patients with subclinical acute rejection compared with those without subclinical acute rejection. Calcineurin inhibitors (CNIs) and anti-CD25 antibody decreased the frequency of Tregs but mTOR inhibitor did not. The frequency of donor-specific IL-10 secreting cells did not correlate with the number of Tregs. The frequency of circulating Tregs in KT recipients is strongly affected by CNIs and anti-CD25 antibody, and a low frequency of Tregs is associated with subclinical acute rejection during the early posttransplant period.
Adult ; CD4-Positive T-Lymphocytes/*immunology ; Enzyme-Linked Immunosorbent Assay ; Female ; Flow Cytometry ; Graft Rejection ; Humans ; Interleukin-10/metabolism ; Interleukin-2 Receptor alpha Subunit/*biosynthesis ; Kidney Failure, Chronic/blood/immunology/*therapy ; Kidney Transplantation/*methods ; Male ; Middle Aged ; Nephrology/*methods ; T-Lymphocytes, Regulatory/*immunology

PURPOSES: To investigate the viral etiology of community-acquired pneumonia in Korean adults, we have detected respiratory viruses (Respiatory syncytial virus, adenovirus, influenza virus and parainfluenza virus) in the way of prospective, multi-center study. METHODS: From July 1997 to April 2000, nasal aspirates or sputum were obtained from adults patients with community pneumonia admitted to the participating hospitals and transferred immediately to the central laboratory in the Seoul National University Children's Hospital. The specimens were divided into three parts. One part was used for indirect immunofluorescent test for respiratory viruses, the other part for the culture of RSV and adenovirus in HEp-2 cell monolayer. Another part was used for the culture of influenza virus and parainfluenza virus in MDCK or LLC- MK2 cell monolayers. RESULTS: Of 317 samples, 32 (10.1%) specimens were positive for viral isolation by indirect IF staining or culture, including one dual-infected specimen (adenovirus and parainfluenza virus). Influenza virus was most commonly detected (16 specimens). Parainfluenza virus, adenovirus and RSV were detected in 10, 4 and 3 patients, respectively. All isolated influenza viruses were type A (H3N2 in 9 patients, H1N1 in 2 and unspecified in 5), and 8 out of 10 parainfluenza virus isolates were type 3. CONCLUSION: Similar to previous foreign reports, a significant portion of community-acquired pneumonia in Korean adult is caused by respiratory viruses. Our data empathized the need of referral system for viral diagnosis and of nationwide investigation on respiratory virus infections.
Adenoviridae ; Adult* ; Diagnosis ; Humans ; Orthomyxoviridae ; Paramyxoviridae Infections ; Pneumonia* ; Prospective Studies ; Referral and Consultation ; Seoul ; Sputum

BACKGROUND: Peroxisome proliferator activated receptor-gamma (PPAR-gamma) is a nuclear receptor that regulate adipocyte differentiation and modulate intracellular insulin-signaling events. As such, PPARgamma is a candidate gene for several human disorders including obesity and type 2 diabetes mellitus. The objective of our study was to examine the relationship between genetic variation of PPARgamma2 and diabetes and obesity in Korean subjects. METHODS: We studied 99 subjects with type 2 diabetes mellitus, 128 obesity patients and 97 controls. Screening for mutation at codon 12 and 115 of PPARgamma2 were carried out by PCR-RFLP analyses. Statistical significance was evaluated by Chi-square test. RESULTS: The allele frequency of the Pro12Ala PPARgamma2 variant were 0.05 in controls, 0.06 in type 2 diabetes group, and 0.07 in obesity group (p=0.47). Pro115Gln variant were only proline homozygote in all groups. Genotype frequencies were also similar and conformed to expectations of the Hardy-Weinberg rule. The presence of PPARgamma2 gene variant was no associated with concentrations of total cholesterol, triglyceride, HDL-cholesterol, and also with fasting glucose. CONCLUSION: We concluded that the Pro12Ala and Pro115Gln PPARgamma2 missense mutation may not be associated with type 2 diabetes mellitus and obesity in Korean patients.
Adipocytes ; Cholesterol ; Codon ; Diabetes Mellitus, Type 2* ; Enzyme-Linked Immunosorbent Assay ; Fasting ; Gene Frequency ; Genetic Variation ; Genotype ; Glucose ; Homozygote ; Humans ; Liver Cirrhosis ; Mass Screening ; Mutation, Missense ; Obesity* ; Peroxisomes ; PPAR gamma* ; Proline ; Triglycerides

BACKGROUND: In a noisy hospital setting, it is not easy to induce hypnosis or sedation calmly. Although the noise stress has been neglected, it seems to disturb a patient's sleep or induction of sedation. Therefore, we tried to evaluate the effects of loud operating room (OR) background noise on bispectral index (BIS) during monitored anesthesia care (MAC) by using an audiometer and BIS monitor. METHODS: Thirty adult patients (ASA class I) were scheduled two times for nasal or dental procedures at an interval of two or three days. In a randomized, cross-over study design, we prospectively compared the BIS values according to the loudness of OR noise in two different depths of sedation during MAC. Propofol target controlled infusion (TCI) was started at a propofol target concentration (CT) 2.0 microgram/ml using a DiprifusorTM with flash mode until a BIS 80 and/or a modified Observer's Assessment of Alertness/Sedation (mOAAS) score of 4 (group 1), and BIS 75 and/or mOAAS score 3 (group 2) was obtained. We evaluated the effect site concentrations and the elapsed time and checked the BIS at 50, 80, 110, and 120 dB of sound pressure level (SPL) in both groups. RESULTS: The BIS at 80, 110 and 120 dB of SPL in group 1 was significantly increased compared to those at 50 dB (P < 0.05). Similarly, the BIS at 110 and 120 dB of SPL in group 1 was significantly increased compared to those at 80 dB (P < 0.05). The patients in their twenties were most susceptible to loud OR noise during sedation. CONCLUSIONS: The loud OR background noise might be possible to interfere with induction of sedation to a degree, which was more noticeable on light to moderate sedation than for deep sedation.
Adult ; Anesthesia* ; Conscious Sedation ; Cross-Over Studies ; Deep Sedation ; Humans ; Hypnosis ; Noise* ; Operating Rooms* ; Propofol ; Prospective Studies

BACKGROUND AND OBJECTIVES: Sinonasal inverted papillomas are benign but topographically aggressive neoplasms that have a high recurrence rate and seem to be associated with malignancy. The etiology of inverted papilloma remains unknown, but some hypotheses suggest that nasal polyps proliferation and chronic inflammation are due to allergy or various infectious lesions. This study was to elucidate the biological characteristics and the role of human papillomavirus (HPV) and Ebstein -Barr virus (EBV) and the expression of p53 protein and proliferating cell nuclear antigen (PCNA) in sinonasal inverted papillomas. MATERIALS AND METHODS: We examined 26 specimens from 26 individuals with normal nasal mucosae (n=10) and inverted papillomas (n=16) to determine the occurance of HPV and EBV infection and the expression of p53 protein and PCNA. RESULTS: Of the 16 Inverted papillomas, HPV DNA was detected in eight cases, HPV 18 was detected in two cases (18%), HPV 16 and HPV 33 were both found in every case (6%), HPV 6 and HPV 16 were coinfected in one case (6%), and other types were found in 3 cases. HPV DNA was not detected in the normal nasal mucosae. EBV DNA was detected in 10 cases (62%) out of 16 inverted papillomas ancl in two cases (20%) of 10 normal nasal mocosae. The altered p53 protein expression was observed in four cases (25%), and positive PCNA staining was detected in four cases (25%) out of 16 inverted papillomas. One positive PCNA staining was detected among 10 normal mucosae. The mean PC10 index was 16.0% in the inverted papillomas group and 4.1% in normal nasal mucosae group. CONCLUSION: An inverse correlation may exist between oncogenic HPV infection and p53 alteration in sinonasa1 inverted papillomas.
DNA ; Epstein-Barr Virus Infections ; Herpesvirus 4, Human* ; Human papillomavirus 16 ; Human papillomavirus 18 ; Human papillomavirus 6 ; Humans* ; Hypersensitivity ; Inflammation ; Mucous Membrane ; Nasal Mucosa ; Nasal Polyps ; Papilloma, Inverted* ; Population Characteristics ; Proliferating Cell Nuclear Antigen* ; Recurrence

Isolated rectal adenomatous polyp without genetic background is rarely found in children. A 4-year and 5 month-old girl was admitted for intermittent bloody stools lasting 4 months. A 1.5x1.2 cm sized rectal polyp was found by air contrast barium enema. Endoscopic polypectomy was performed without complications. In histopathologic examination, it was found to be a tubulovillous adenoma. Typical radiologic, colonoscopic, and pathological pictures are presented.
Adenoma* ; Adenomatous Polyps* ; Barium ; Child* ; Enema ; Female ; Humans ; Infant ; Polyps ; Rectum*