A case report of breakthrough infection with the SARS-CoV-2 delta variant and household transmission: Role of vaccination, anti-spike IgG and neutralizing activity.

There have been several reports of breakthrough infections, which are defined as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections among individuals who had received at least two doses of vaccine at least 14 days before the onset of infection, but data on the antibody titers, including SARS-CoV-2 neutralizing antibody activity, and the clinical course of individuals with breakthrough infections are limited. We encountered a case of breakthrough infection with the SARS-CoV-2 delta variant in a 31-year-old female healthcare worker (the index case, Case 1) and a secondary case (Case 2) in her unvaccinated 33-year-old husband. We studied the role of the anti-spike immunoglobulin G (IgG) and neutralizing antibody activity in the two case patients. Case 1 had high anti-spike IgG detected on day 3 of the illness, with low neutralizing antibody activity. The neutralizing antibody activity started to increase on day 5 of the illness. In Case 2 both the anti-spike IgG and the neutralizing antibody activity remained low from days 4-11 of illness, and the anti-spike IgG gradually increased from day 9. In Case 1, the fever broke within 4 days of onset, coinciding with the rise in neutralizing antibodies, whereas the fever took 7 days to resolve in Case 2. SARS-CoV-2 infection can occur even in vaccinated individuals, but vaccination may contribute to milder clinical symptoms because neutralizing antibodies are induced earlier in vaccinated individuals than in unvaccinated individuals.

Isolation of human monoclonal antibodies with neutralizing activity to a broad spectrum of SARS-CoV-2 viruses including the Omicron variants.

Monoclonal antibody therapy is a promising option for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, and a cocktail of antibodies (REGN-COV) has been administered to infected patients with a favorable outcome. However, it is necessary to continue generating novel sets of monoclonal antibodies with neutralizing activity because viral variants can emerge that show resistance to the currently utilized antibodies. Here, we isolated a new cocktail of antibodies, EV053273 and EV053286, from peripheral blood mononuclear cells derived from convalescent patients infected with wild-type SARS-CoV-2. EV053273 exerted potent antiviral activity against the Wuhan wild-type virus as well as the Alpha and Delta variants in vitro, whereas the antiviral activity of EV053286 was moderate, but it had a wide-range of suppressive activity on the wild-type virus as well as the Alpha, Beta, Delta, Kappa, Omicron BA.1, and BA.2 variants. With the combined use of EV053273 and EV053286, we observed similar inhibitory effects on viral replication as with REGN-COV in vitro. We further assessed their activity in vivo by using a mouse model infected with a recently established viral strain with adopted infectious activity in mice. Independent experiments revealed that the combined use of EV053273 and EV053286 or the single use of each monoclonal antibody efficiently blocked infection in vivo. Together with data showing that these two monoclonal antibodies could neutralize REGN-COV escape variants and the Omicron variant, our findings suggest that the EV053273 and EV053286 monoclonal antibody cocktail is a novel clinically applicable therapeutic candidate for SARS-CoV-2 infection.

Multisystem Inflammatory Syndrome in Adult after First Dose of mRNA Vaccine.

A 32-year-old man in Japan experienced respiratory failure after receiving the first dose of coronavirus disease (COVID-19) vaccine. He was treated with noninvasive ventilation and corticosteroids. Serologic test results suggested previous COVID-19; therefore, he received a diagnosis of multisystem inflammatory syndrome. COVID-19 vaccination could be a trigger for this condition.

Case Report: Changes in Cytokine Kinetics During the Course of Disease in a Japanese Patient With Multisystem Inflammatory Syndrome in Children.

Multisystem inflammatory syndrome in children (MIS-C) is a severe disease that is reportedly linked to coronavirus disease 2019. Affected patients present with gastrointestinal symptoms and cardiovascular dysfunction, in addition to Kawasaki disease-like features, suggesting the potential for overlapping disease mechanisms. Kawasaki disease has been reported among individuals of East Asian ethnicities, whereas there is minimal clinical literature regarding the occurrence of MIS-C among individuals of Asian ethnicities. A few reports thus far have described changes in cytokine kinetics during the course of disease in patients with MIS-C. We followed the temporal cytokine kinetics in a 9-year-old Japanese girl who exhibited a classical trajectory of MIS-C. The patient exhibited right cervical swelling and pain, abdominal pain, vomiting, and lip reddening, which developed 31 days after she was diagnosed with severe acute respiratory syndrome coronavirus-2 infection. The patient was diagnosed with Kawasaki disease on her fifth day of illness; because she fulfilled the criteria for MIS-C, she was also diagnosed with this disease on her fifth day of illness. Her fever rapidly resolved upon administration of intravenous immunoglobulin, aspirin, and prednisolone. On the patient's sixth day of illness, she developed acute myocarditis, which was treated with two diuretics and one vasodilator; the myocarditis ameliorated within a few days. Analyses of temporal kinetics for 71 serum cytokines revealed several patterns of cytokine changes that were consistent with the patient's clinical course of disease. Importantly, there was a clear distinction between cytokines that did and did not decrease rapidly following post-treatment fever resolution. These findings may be useful for the assessment of disease status and selection of therapy in patients with similar symptoms; they may also provide insights for basic and clinical research regarding MIS-C.

Retrotransposition and senescence in mouse heart tissue by viral protein R of human immunodeficiency virus-1.

Combination antiretroviral therapy (cART) has greatly improved the prognosis of patients with human immunodeficiency virus type-1 (HIV-1) infection. However, cardiovascular disease (CVD) remains a serious issue even in the post-cART era. Viral protein R (Vpr), an accessory gene product of HIV-1, exerts pleiotropic activities such as the induction of DNA damage signals, apoptosis by mitochondrial membrane depolarization, G2/M-phase cell cycle abnormalities, and retrotransposition. Importantly, some of these cellular responses are induced by the trans-acting activity of Vpr. Recently, we established an enzyme-linked immunosorbent assay to detect Vpr and reported that about 22% of blood samples from 100 HIV-1-positive patients were positive for Vpr. Here, we investigated the biological effects of recombinant Vpr (rVpr) in vivo. We observed that repeated injections of rVpr increased the copy number of long interspersed element-1 (L1) in the heart genome in mice. rVpr also increased the number of cells positive for senescence-associated ß-galactosidase (SA-ß-gal) and fibrosis in the heart. Notably, co-administration of a reverse transcriptase inhibitor reduced the number of rVpr-induced SA-ß-gal-positive cells and fibrosis concomitantly with the attenuation of L1 retrotransposition. Interestingly, a Vpr mutant defective for mitochondrial dysfunction also induced heart senescence and increased L1 copy number. Together with a recent report that L1 retrotransposition functions as a molecular basis of senescence, our current data suggest that rVpr-induced L1 retrotransposition is linked with senescence in heart tissue. We would propose that Vpr in the bloodstream may be one of risk factors for CVD, and that its monitoring will lead to well understanding of the heterogeneity and multifactorial mechanisms of CVD in HIV-1 patients.

Modulation of long interspersed nuclear element-1 in the mouse hippocampus during maturation.

BACKGROUND: Retrotransposition of long interspersed nuclear element-1 (L1-RTP) is proposed to contribute to central nervous system (CNS) plasticity by inducing mosaicism of neuronal cells. Clinical studies have identified increased L1 copy numbers in the brains of patients with psychiatric disorders. These observations implicate that L1-RTP is important for neurogenesis and that its deregulation represents a risk factor for mental disorders. However, no supportive evidence is available for understanding the importance of L1-RTP in CNS function. FINDINGS: To explore the physiological role of L1-RTP in CNS, we examined the L1 copy number during maturation. Interestingly, the L1 copy number increased after birth in the mouse hippocampus, but not the frontal lobe, with maximal copy numbers found in 8-week-old mice. This age-dependent L1 increase was abolished by administration of a reverse-transcriptase inhibitor, stavudine (d4T), which showed no toxic effects. Notably, the age-dependent L1 increase was attenuated by post-weaning social isolation (SI) stress, a well-known intervention for inducing psychiatric disorders in mice, or deletion of the NR2A gene that encodes a subunit of the glutamate receptor. Moreover, the negative effects of SI stress on L1-RTP were partially restored by environmental enrichment with voluntary running, but not by fluoxetine, a commonly used anti-psychiatric drug. Finally, behavioral experiments revealed that learning memory was defective in d4T-treated mice, which was similarly observed in mice raised under SI stress. CONCLUSION: We detected the modulation of L1-RTP in the hippocampus during maturation of the CNS. In a recent study, we demonstrated that stimulants such as methamphetamine and cocaine were active in the induction of L1-RTP in neuronal cells, and previous studies have shown that NR2A-deficient mice are susceptible to mental abnormality. Herein, our data support the notion that the age-dependent modulation of L1-RTP is involved in genome differentiation in the hippocampus, and that modulation defects are linked to the development of psychiatric disorders.

A possible port of entry into the eye of dog during erratic canine heartworm (Dirofilaria immitis) parasitism.

A dog was suspected of suffering from ectopic Dirofilaria immitis infection, because a large white nematode worm was detected in the anterior chamber of the left eye. A cylinder-shaped fibrin sac in the anterior chamber was found in the eye of the dog by slit lamp microscopy. After successful surgical removal of the worm, the corneal wound produced by the keratotomy healed in a short period. The worm was estimated to be extremely young, 5th-stage-immature male D. immitis, equivalent to a 90-120-day-old worm postinfection, by close morphological measurement and an experimental infection study. Thus, an immature worm can exhibit erratic parasitism in a host's eye. The fibrin sac was considered to be a trace of the invasion route, and the cornea may have been the port of entry into the anterior chamber of the eye in the erratic migration of D. immitis.

Preliminary genome-wide association study of bipolar disorder in the Japanese population.

Recent progress in genotyping technology and the development of public databases has enabled large-scale genome-wide association tests with diseases. We performed a two-stage genome-wide association study (GWAS) of bipolar disorder (BD) in Japanese cohorts. First we used Affymetrix 100K GeneChip arrays in the analysis of 107 cases with bipolar I disorder and 107 controls, and selected markers that were nominally significant (P < 0.01) in at least one of the three models (1,577 markers in total). In the follow-up stage, we analyzed these markers using an Illumina platform (1,526 markers; 51 markers were not designable for the platform) and an independent sample set, which consisted of 395 cases (bipolar I + II) and 409 controls. We also assessed the population stratification of current samples using principal components analysis. After the two-stage analysis, 89 markers remained nominally significant (allelic P < 0.05) with the same allele being consistently over-represented in both the first and the follow-up stages. However, none of these were significant after correction for multiple-testing by false discovery rates. Sample stratification was virtually negligible. Collectively, this is the first GWAS of BD in the Japanese population. But given the small sample size and the limited genomic coverage, these results should be taken as preliminary.

Bowel obstruction due to diaphragmatic hernia in an elder child after pediatric liver transplantation.

A 10-yr-old boy with end-stage liver cirrhosis due to Wilson's disease received a living donor liver transplantation (LDLT) at our institution. The donor was his father and the graft was a left lateral segment. The liver transplantation procedure and the postoperative course were uneventful. Two months after the procedure, he developed a first episode of bowel obstruction that was treated with conservative therapy. During a second episode of bowel obstruction, he also presented respiratory distress. A plain chest X-ray revealed the presence of small intestine loops in the right thoracic cavity and bowel obstruction due to diaphragmatic hernia was diagnosed. Repair of the diaphragmatic hernia was performed and the patient has been doing well after the surgery. Diaphragmatic hernia after LDLT is rare but should be recognized as a possible complication when a left lobe or a left lateral segment graft is used.

Feasibility of using the cystic duct for biliary reconstruction in right-lobe living donor liver transplantation.

Duct-to-duct biliary reconstruction has been introduced in adult living donor liver transplantation (LDLT). In right-lobe grafts, however, the presence of two or three separated bile duct orifices is not rare and makes an alternative approach for reconstruction necessary. We used the cystic duct for one of the anastomoses in biliary reconstruction for 5 right-lobe living donor liver transplants with two separated ducts. Before the anastomosis, the inside lumen of the cystic duct was straightened with a metal probe. Two external drainage tubes were placed in all recipients, and posttransplant cholangiography through the tubes approximately one month after transplantation showed no leakage or stricture at any of the anastomotic sites. The drainage tubes were removed between 17 and 37 weeks after transplantation. All of the patients except one who died of chronic rejection have been doing well without any late biliary complications during follow-up periods ranging from 10 to 28 months after transplantation. In conclusion, our results indicate that biliary reconstruction using the cystic duct is feasible and safe for living donor liver transplantation and that external drainage tubes may be effective for prevention of complications.

Living domino liver transplantation in an adult with congenital absence of portal vein.

Congenital absence of the portal vein (CAPV) is a rare malformation of the splanchnic venous system. Although CAPV is usually detected in the pediatric age group, our patient was a 35-year-old woman. She had been diagnosed with CAPV in 1996 when she was 27 years old. In 1998, she was placed on hemodialysis due to chronic renal failure. After several episodes of encephalopathy in 2002, liver transplantation (LT) was recommended to her and her family. Since there was no suitable living donor candidate, she was put on the waiting list for a deceased donor liver transplant in Japan. In 2004, her ammonia level increased to around 300 microg/dl, and she went into a coma lasting for three days. After recovering from this event, she underwent a living domino transplantation using a whole liver donated by a familial amyloid polyneuropathy (FAP) patient. Her portal vein, which had drained directly into the inferior vena cava (IVC), was transected together with a cuff of the IVC wall and anastomosed to the graft liver portal vein in an end-to-end fashion. In conclusion, liver transplantation proved to be a safe and effective way to save this patient and improve her quality of life.

Duct-to-duct biliary reconstruction in pediatric living donor liver transplantation.

The results of duct-to-duct biliary reconstruction in six pediatric patients who received a living donor liver transplant aged from 2 months to 11 yr old are reported. The graft was either entire or a part of the left lateral segments. The orifice of the bile duct of the graft was anastomosed to the recipients' hepatic duct in an end-to-end fashion by interrupted suture using 6-0 absorbable material. A transanastomotic external stent tube (4 Fr) was passed through the stump of the recipients' cystic duct. Mean time for reconstruction was 24 min. All the recipients survived the operation and reinitiated oral intake on postoperative day 3. There were no early biliary complications. One 5-yr-old boy suffered from an anastomotic stenosis 9 months after transplantation. He underwent re-anastomosis by Roux-en Y (R-Y) procedure and recovered uneventfully. Duct-to-duct anastomosis in pediatric living donor liver transplantation has benefits while the complication rate is comparable to R-Y reconstruction.

Rescue for rare complications of the hepatic artery in living donor liver transplantation using grafts of autologous inferior mesenteric artery.

This report describes two rescued cases with rare complications of the hepatic artery in living-donor liver transplantation (LDLT). In both cases a segment of the autologous inferior mesenteric artery (IMA) was successfully used as an arterial graft for re-vascularization under microsurgery. The first case was that of a pseudoaneurysm of the hepatic artery, which caused massive gastrointestinal bleeding. The hepatic arteries of the pre- and post-aneurysm were divided, and the arterial graft from the recipient's IMA was interposed for reconstruction. The second case was that of an intimal dissection of the recipient's hepatic artery. Because the dissection extended to the root of the common hepatic artery, the autologous IMA was interposed between the donor's hepatic artery and the proximal stump of the recipient's splenic artery. Reconstruction using the arterial graft of the autologous IMA is feasible for re-vascularization of the hepatic artery in liver transplantation.

Early graft failure due to a veno-occlusive disease after a pediatric living donor liver transplantation.

A 10-month-old boy with biliary atresia after Kasai procedure underwent a living donor liver transplantation (LDLT). Five days after the LDLT, high fever and increased ascites followed by poor bile drainage was accompanied by elevation of serum liver enzymes. Liver biopsy showed occlusion of the central veins by fibro-edematous endothelium and submassive necrosis of the parenchyma. Veno-occlusive disease (VOD) was suspected, and re-LDLT was urgently performed because of deterioration of hepatic failure. There are few cases of VOD after liver transplantation and this is the first one in an infant after LDLT.

[Analysis of the fyn kinase gene in Alzheimer's disease and schizophrenia].

Reelin is a protein which plays an important role in cell construction and proliferation of neurons during the development of the central nervous system. Several lines of evidence suggest a possible role for reelin-related genes in the etiology of neurodevelopmental as well as neurodegenerative diseases. It is possible that variations in reelin-related genes (Reelin, VLDLR, FYN, CNRs, a3b1INTEGRIN, mDAB1) may be involved in the pathogenesis of schizophrenia and Alzheimer's disease. We have been conducting a systematic survey of the association of reelin-related gene polymorphisms with these disorders. Previously, we examined the association of the triplet repeats of the reelin and VLDLR gene with schizophrenia. We found no significant association of schizophrenia with the trinucleotide repeat polymorphism of the reelin nor VLDLR genes (Akahane et al. 2002). In this study, we performed an allelic association analysis in Alzheimer's disease and schizophrenia with three polymorphisms of the fyn gene reported by Ishiguro et al (2000). Diagnosis was based on DSM-IV and NINCDS-ADRDA. We found no significant differences in genotype distribution or allelic frequency between patient and control groups. Thus, it is unlikely that these polymorphisms play an important role in the pathogenesis of Alzheimer's disease or schizophrenia.