A Rare Manifestation of IgG4-Related Disease and Secondary Hypereosinophilic Syndrome: A Case Report.

We report a case of IgG4-related disease with marked eosinophilia. A 79-year-old woman was admitted due to diarrhea, and weight loss. Cervical lymphadenopathy, bilateral submandibular glands swelling, anemia (Hb8.5g/dl), hypereosinophilia (9,750/µL), and elevated serum creatinine (1.57 mg/dL), pancreatic amylase (191 IU/L), and IgG4 (3,380 mg/dL) were found. Diffusion-weighted image on MRI showed high intensity signals inside of both the pancreas and the kidney. The echogram of submandibular glands revealed cobblestone pattern. Kidney biopsy revealed acute tubulointerstitial nephritis. Biopsies of lip, gastrointestinal tract and bone marrow showed infiltration of lymphoplasmacytic cells and IgG4 positive plasma cells (30-67/HPF). Gastrointestinal and bone marrow biopsies also showed eosinophilic infiltration. Adrenal insufficiency, rheumatic disease, tuberculosis, parasite infection, drug induced eosinophilia, and eosinophilic leukemia were all ruled out. We started treatment with 40mg of prednisolone and her general condition rapidly improved. The eosinophil count, serum IgG4, and serum creatinine decreased. We gradually tapered prednisolone and maintained 5mg/day. During the 5 years of treatment, she had no recurrence of the symptom. According to the 2019 American College of Rheumatology/European League Against Rheumatism classification criteria for IgG4-related disease, eosinophils > 3000/µL is one of the exclusion criteria. If we comply this criterion, the diagnosis of IgG4-related disease should be avoided. However, our case fit the diagnostic criteria of type I autoimmune pancreatitis, IgG4-related sialadenitis and global diagnosis of IgG4-related disease. We finally diagnosed our case as IgG4-related disease with secondary hypereosinophilic syndrome. This case suggests that IgG4-related disease with eosinophils > 3000/µL does exist in the real world.

Cardiac Tamponade as an Initial Manifestation of Diffuse Large B-cell Lymphoma One Year after IgG4-related Disease in Remission.

A 65-year-old man with multiple lymphadenopathies was diagnosed with IgG4-related disease (IgG4-RD) based on findings of a cervical lymph node biopsy and an elevated serum IgG4 level. Treatment was initiated after the onset of autoimmune pancreatitis, and he achieved remission. He developed diffuse large B-cell lymphoma one year later. Pericardial involvement of lymphoma resulted in cardiac tamponade, and he died before histopathological confirmation of lymphoma was made due to a lethal arrhythmia caused by massive involvement of lymphoma into the myocardium. Because patients with IgG4-RD might have an increased risk of malignant diseases, including lymphoma, histopathological examinations should be considered at any time during the course of IgG4-RD.

The relation between vaccination status and referral to a consultation-liaison psychiatry service for hospitalized patients with COVID-19.

BACKGROUND: Previous studies have shown that patients with Coronavirus Disease 2019 (COVID-19) are likely to be affected by delirium and other psychiatric complications. We aimed to evaluate the relation between COVID-19 vaccination status and referral of patients hospitalized with COVID-19 for consultation-liaison psychiatry services. METHOD: From the medical records used for this retrospective, single hospital-based study, 576 patients were identified who were over 18 years-of-age and hospitalized with a diagnosis of COVID-19 between March 2020 and March 2022. The data of 531 for whom the vaccine history was obtained from the medical records were available for analysis: 455 without and 76 with referral to consultation-liaison psychiatry. A history of COVID-19 vaccination at least two times was used in the analysis of the odds for referral to liaison psychiatric consultation: 95% confidence interval (CI) in multivariable logistic regression. The adjustment factors included sex, age, body mass index (BMI), severity of COVID-19, C-reactive protein level, medical history, and therapeutic factors such as the use of remdesivir, steroids, or mechanical ventilation. RESULTS: The prevalence of psychiatric consultation was 14.3%. Patients without vaccination had a 7-times greater OR (95%CI:2.08-23.58) than vaccinated patients for a referral for consultation-liaison psychiatry services after adjusting for confounding factors. CONCLUSION: Non-vaccination was associated with a greater likelihood of referral for consultation-liaison psychiatry service among these hospitalized Japanese patients with COVID-19, even after adjusting for clinical and therapeutic factors. It is possible that vaccination greatly lessens the need for the referral of COVID-19 patients for consultation-liaison psychiatry services.

Familial immune-mediated aplastic anaemia in six different families.

We studied the pathophysiology of aplastic anaemia (AA) in six different pairs of relatives without a family history of hematologic disorders or congenital AA. Five and four of the six pairs shared the HLA-DRB1*15:01 and B*40:02 alleles, respectively. Glycosylphosphatidylinositol-anchored protein-deficient blood cells were detected in eight of the 10 patients evaluated. In a mother-daughter pair from one family, flow cytometry detected leukocytes lacking HLA-A2 due to loss of heterogeneity in chromosome 6p. Whole-exome sequencing of the family pair revealed a missense mutation in MYSM1. These results suggest that genetic inheritance of immune traits might underlie familial AA in some patients.

Differences in the presentation of COVID-19-related psychosocial stress and general psychological distress and the relation between the number of care days and these symptoms among Japanese ward staff working exclusively with COVID-19 and support staff.

BACKGROUND: Psychological distress has been frequently observed in frontline healthcare workers under stress during the coronavirus disease 2019 (COVID-19) epidemic; however, it is unclear if there are differences in the stress and symptoms experienced by staff members who work exclusively in a COVID-19 ward and support staff temporarily deployed to a COVID-19 ward. The present study investigated psychosocial stress specific to the care for patients with COVID-19 and psychological distress among ward staff working exclusively with COVID-19 and temporary support staff. METHODS: The participants were full-time nurses and doctors working in COVID-19 wards or the ICU who provided face-to-face care to patients with COVID-19 during the COVID-19 outbreak in February of 2021. The data of 67 staff members (21 exclusively working with Covid-19 patients (group A) and 46 in the temporary support group (group B)) was available for study. Psychosocial stress specific to healthcare professionals during this COVID-19 outbreak (Tokyo Metropolitan Distress Scale for Pandemic [TMDP]) and general psychological distress (K6) were assessed. RESULTS: The K6 score was significantly lower in group B than in group A (p = .006), but no significant difference was found in the total score of TMDP or its subscales. Positive correlations were found between TMDP and K6 for group B (p = .011), as was the number of days of care on TMDP-social (rs = .456, p = .001). CONCLUSION: Even though support staff members experienced lower psychological distress than staff working exclusively with COVID-19, COVID-19-related psychosocial stress specific to HCWs was comparable. The support staff also presented psychological distress associated with psychosocial stress specific to healthcare professionals during this COVID-19 outbreak, and the COVID-19-related social stress was enhanced as the number of working days increased. Our results show that all staff, not only those working exclusively with COVID-19 patients but also other support staff should be provided with care focusing on COVID-19-related psychosocial occupational stress.

Occupational stress, psychological distress, physical symptoms, and their interrelationships among frontline nurses caring for COVID-19 patients in Japan.

This study aimed to identify occupational stress, psychosomatic symptoms, psychological distress, and their correlations among frontline nurses during and after the first peak of the coronavirus disease 2019 (COVID-19) outbreak in Japan. Sixteen frontline nurses, aged 25 to 52 years, working in a ward with COVID-19 patients participated in this study. Two months after the peak of the first wave of the COVID-19 outbreak in Japan, the COVID-19-related occupational stress scale (COS; questionnaire items: fear of infection and increased workload) and physical symptom scale (PS; questionnaire items: gastrointestinal symptoms, pain, appetite loss, and insomnia) were assessed. The degree of general psychological distress was evaluated using the 6-item Kessler Scale (K6). Simultaneously, participants were asked to recall their condition during the peak period of the first wave and rate it using the same scale. K6 was positively correlated with COS and PS during the peak period (rs = 0.574, P = .020 and rs = 0.587, P = .017, respectively). Increased workload was positively correlated with the K6 score both during and after the peak period (rs = 0.869, P < .001 and rs = 0.732, P = <.001, respectively) and was positively correlated with insomnia during the peak period (rs = 0.498, P < .05). The COS, PS, and K6 scores during the peak period were significantly higher than those after the peak period. Psychological distress at the peak was associated with PS and occupational stress. An increased workload during peak periods can cause psychological distress and insomnia. The occupational stress, PS, and psychological distress of nurses working in COVID-19 wards improved after the peak of COVID-19.

Compassion fatigue in a health care worker treating COVID-19 patients: a case report.

BACKGROUND: Doctors treating COVID-19 are under extreme stress. It was reported that healthcare workers providing palliative care could present elevated levels of compassion fatigue. We herein report a case if the attending doctor of severe COVID-19 cases who felt extreme psychological difficulty and suffered from compassion fatigue. CASE PRESENTATION: A 29-year-old female doctor presented with anxiety and insomnia. Her stress from overwork was exacerbated during the treatment of two related COVID-19 patients, a 47-year-old man with COVID-19 and his 76-year-old mother, who suffered acute stress disorder after the death of her son. The mother first refused treatment, but with psychiatric intervention she was able to recover and be discharged. In the course of these cases of COVID-19, their attending physician felt psychological distress and presented with insomnia and anticipatory anxiety due to the poor prognosis of the mother. After being presented with a systematic approach to improve her work situation by the hospital executive staff and undergoing psychotherapy for compassion fatigue, she recovered and was able to return to work. CONCLUSIONS: We report a physician in charge of severe cases of COVID-19, who suffered an adverse impact on her mental health. Excessively empathic engagement in the care of patients who do not survive and their relatives provides high risk for compassion fatigue. The stress-related distress of HCWs should be more widely recognized in order to improve support systems for them.

MERIT40-dependent recruitment of tankyrase to damaged DNA and its implication for cell sensitivity to DNA-damaging anticancer drugs.

Tankyrase, a member of the poly(ADP-ribose) polymerase (PARP) family, regulates various intracellular responses, such as telomere maintenance, Wnt/ß-catenin signaling and cell cycle progression through its interactions with multiple target proteins. Tankyrase contains a long stretch of 24 ankyrin repeats that are further divided into five subdomains, called ANK repeat clusters (ARCs). Each ARC works as an independent ligand-binding unit, which implicates tankyrase as a platform for multiple protein-protein interactions. Furthermore, tankyrase distributes to various intracellular loci, suggesting potential distinct but yet unidentified physiological functions. To explore the novel functions of tankyrase, we performed liquid chromatography-mass spectrometry analysis and identified the BRE-BRCC36-MERIT40 complex, a regulator of homologous recombination, as tankyrase-binding proteins. Among the complex components, MERIT40 was directly associated with tankyrase via a tankyrase-binding consensus motif, as previously reported. In X-ray-irradiated non-small cell lung cancer cells, tankyrase localized to DNA double-stranded break sites in a MERIT40-dependent manner. MERIT40 knockdown increased the cell sensitivity to X-ray, whereas the wild-type, but not the tankyrase-unbound mutant, MERIT40 rescued the phenotype of the knockdown cells. Tankyrase inhibitors, such as G007-LK and XAV939, increased the cellular sensitivity to X-ray irradiation and anticancer drugs that induce DNA double-stranded breaks. These observations suggest that tankyrase plays a role in the DNA damage repair response and implicates a potential therapeutic utility of tankyrase inhibitors in combination treatments with DNA-damaging anticancer drugs.

Successful Treatment of Hemophagocytic Lymphohistiocytosis Associated with Low-risk Myelodysplastic Syndrome by Azacitidine.

Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening syndrome that occurs as a complication in many clinical settings. Malignancy-associated HLH develops in patients with hematopoietic neoplasms, particularly in those with lymphoma, and its development in those with myelodysplastic syndrome (MDS) is uncommon. We herein report a case of HLH in a patient with low-risk MDS that was successfully treated with azacitidine. The prevalence of immune abnormalities among MDS patients and the immune effects of azacitidine have recently been elucidated, suggesting that MDS-associated HLH occurs as a result of immune impairment, and azacitidine improves this condition by restoring the immune system.

Reduced-intensity conditioning followed by cord blood transplantation in a patient with refractory folliculotropic mycosis fungoides.

Advanced-stage mycosis fungoides (MF) has a generally poor prognosis. Allogeneic hematopoietic stem cell transplantation improves the outcome of advanced-stage MF. Recently, cord blood has been used as an alternative stem cell source; however, there are few reports of MF patients treated using cord blood transplantation. Here, we report a rare case of refractory folliculotropic MF, which was treated with reduced-intensity conditioning followed by cord blood transplantation.

Successful treatment of primary plasma cell leukaemia by allogeneic stem cell transplantation from haploidentical sibling.

Primary plasma cell leukaemia (PCL) is a rare, aggressive neoplasm of plasma cell dyscrasia. Conventional chemotherapy is usually ineffective, with an overall survival of only 8 months. Here, we describe a 42-year-old man with primary PCL, who was successfully treated with haploidentical (2-HLA loci mismatched) haematopoietic stem-cell transplantation (HSCT). To overcome the human leukocyte antigen (HLA) disparity, in vivo T-cell purging by the pre-transplant administration of antithymocyte globulin followed by a conventional prophylactic treatment against graft-versus-host disease (GVHD) resulted in an avoidance of severe GVHD as well as infectious complications. The patient has maintained complete remission for 13 months after haploidentical HSCT, indicating that a graft-versus-PCL effect might be preserved. Haploidentical HSCT can be a potentially curative treatment for patients with primary PCL who do not have an HLA-identical donor.

Crystallization and preliminary crystallographic analysis of hygromycin B phosphotransferase from Escherichia coli.

Aminoglycoside antibiotics, such as hygromycin, kanamycin, neomycin, spectinomycin and streptomycin, inhibit protein synthesis by acting on bacterial and eukaryotic ribosomes. Hygromycin B phosphotransferase (Hph; EC 2.7.1.119) converts hygromycin B to 7''-O-phosphohygromycin using a phosphate moiety from ATP, resulting in the loss of its cell-killing activity. The Hph protein has been crystallized for the first time using a thermostable mutant and the hanging-drop vapour-diffusion method. The crystal provided diffraction data to a resolution of 2.1 A and belongs to space group P3(2)21, with unit-cell parameters a = b = 71.0, c = 125.0 A. Crystals of complexes of Hph with hygromycin B and AMP-PNP or ADP have also been obtained in the same crystal form as that of the apoprotein.

Reconstitution of HLA-A*2402-restricted cytomegalovirus-specific T-cells following stem cell transplantation.

Cytomegalovirus (CMV)-specific immune reconstitution early after stem cell transplantation (SCT) was evaluated prospectively by detecting CD8+ T-cells, which recognize the peptide QYDPVAALF in the context of HLA-A*2402. Fifteen allogeneic SCT recipients were included in the study. All recipients and donors were seropositive for CMV and had the HLA-A*2402 allele. CMV-specific T-cells were detected as early as 1 month after transplantation, and their numbers increased to peak levels 2 to 5 months after transplantation. The numbers of CMV-specific T-cells in patients who developed grade II to IV acute graft-versus-host disease (GVHD) and received corticosteroids for acute GVHD were low in the early period after allogeneic SCT. There was a trend toward earlier reconstitution of CMV-specific CD8+ T-cells in allogeneic peripheral blood SCT (PBSCT) patients than in allogeneic bone marrow transplantation patients. The contribution of T-cells in the graft to the recovery of CMV-specific immune responses was also suggested by the finding that the reconstitution of CMV-specific CD8+ T-cells was delayed in CD34-selected autologous PBSCT compared with unpurged autologous PBSCT. The reconstitution of CMV-specific CD8+ T-cells was delayed in patients with CMV disease or recurrent CMV reactivation. These observations suggest that the detection of CMV-specific T-cells with an HLA-peptide tetramer is useful to assess immune reconstitution against CMV and to identify patients at risk for CMV disease or recurrent CMV reactivation after SCT.