Anomalous spin precession systematic effects in the search for a muon EDM using the frozen-spin technique.

At the Paul Scherrer Institut (PSI), we are developing a high-precision apparatus with the aim of searching for the muon electric dipole moment (EDM) with unprecedented sensitivity. The underpinning principle of this experiment is the frozen-spin technique, a method that suppresses the spin precession due to the anomalous magnetic moment, thereby enhancing the signal-to-noise ratio for EDM signals. This increased sensitivity enables measurements that would be difficult to achieve with conventional g-2 muon storage rings. Given the availability of the 125MeV/c muon beam at PSI, the anticipated statistical sensitivity for the EDM after a year of data collection is 6×10-23e·cm. To achieve this goal, it is imperative to do a detailed analysis of any potential spurious effects that could mimic EDM signals. In this study, we present a quantitative methodology to evaluate the systematic effects that might arise in the context of the frozen-spin technique utilised within a compact storage ring. Our approach involves the analytical derivation of equations governing the motion of the muon spin in the electromagnetic (EM) fields intrinsic to the experimental setup, validated through numerical simulations. We also illustrate a method to calculate the cumulative geometric (Berry's) phase. This work complements ongoing experimental efforts to detect a muon EDM at PSI and contributes to a broader understanding of spin-precession systematic effects.

Collegiate baseball pitchers demonstrate a relationship between ball velocity and elbow varus torque, both within and across pitchers.

High elbow varus torque during baseball pitching has been identified as a potential cause of ulnar collateral ligament injury in baseball pitchers. In general, elbow varus torque increases as ball velocity increases across pitchers. However, studies incorporating within-subject analyses report that not all professional pitchers have a positive relationship between elbow varus torque and ball velocity (T-V relationship). It remains unknown whether collegiate pitchers show the same trend as professionals in their T-V relationships. The current study investigated the T-V relationship of collegiate pitchers focusing on both across and within pitchers. Division 1 collegiate pitchers (n = 81) were assessed for elbow torque and ball velocity during pitching. Both across- and within-pitcher T-V relationships were significant (p < 0.05) using linear regression. However, more variance in elbow varus torque was explained using the within-pitcher relationship (R2 = 0.29) than the across-pitcher relationship (R2 = 0.05). Of the 81 pitchers, nearly half (n = 39) had significant T-V relationships, while the other half (n = 42) did not. Our findings indicate that the T-V relationship should be assessed on an individual basis as T-V is pitcher-specific.

Successful Steroid Therapy for Lipoid Pneumonia Developing After Allogeneic Hematopoietic Stem Cell Transplant: A Case Report.

Lipoid pneumonia is an uncommon noninfectious inflammatory lung disease characterized by lipid deposition in the alveoli, and its etiology and treatment have not been elucidated. We report the case of a 32-year-old woman who developed lipoid pneumonia 9 months after allogeneic hematopoietic stem cell transplant for chronic myelogenous leukemia in lymphoid blast crisis. She complained of progressive cough and dyspnea shortly after discontinuation of immunosuppressive therapy given for graft-vs-host disease. Computed tomography demonstrated diffuse ground-glass opacities in the lungs, and pulmonary function test revealed restrictive impairment. Bronchoalveolar lavage fluid showed milky appearance, and transbronchial lung biopsy specimen revealed foamy macrophages infiltrating the alveoli. Based on these findings, she was diagnosed as having lipoid pneumonia. Prednisolone (1 mg/kg/d) promptly improved the symptoms, pulmonary shadows, and pulmonary function. The findings and clinical course of this case suggest that lipoid pneumonia should be recognized as one of the pulmonary complications of allogeneic hematopoietic stem cell transplantation.

Expression of Stem Cell Factor in Feline Mast Cell Tumour.

Stem cell factor (SCF) is a ligand of the molecule Kit, which is expressed in mast cells and is important for mast cell proliferation, migration and survival. Mast cell tumours (MCTs) are associated with mutations of c-kit, a proto-oncogene encoding the Kit protein. In this study, we examined SCF expression in 23 samples of feline MCTs. SCF expression was detected in 10 cutaneous MCTs and a case of splenic mastocytosis. In the cutaneous MCTs, SCF-positive tumour cells were located at the margins. Kit was expressed in eight of the 10 cutaneous cases of SCF-expressing MCTs. In these cases, Kit-positive cells were located near to SCF-positive cells, and SCF/Kit double-positive tumour cells were found. Ki67-positive tumour cells were not found near to SCF-positive cells. These results suggest that SCF autocrine/paracrine mechanisms are involved in the expansion of cutaneous MCTs, but not in tumour proliferation.

Oncolytic reovirus therapy: Pilot study in dogs with spontaneously occurring tumours.

Oncolytic virotherapy is a novel treatment involving replication-competent virus in the elimination of cancer. We have previously reported the oncolytic effects of reovirus in various canine cancer cell lines. This study aims to establish the safety profile of reovirus in dogs with spontaneously occurring tumours and to determine a recommended dosing regimen. Nineteen dogs with various tumours, mostly of advanced stages, were treated with reovirus, ranging from 1.0 × 108 to 5.0 × 109 TCID50 given as intratumour injection (IT) or intravenous infusion (IV) daily for up to 5 consecutive days in 1 or multiple treatment cycles. Adverse events (AEs) were graded according to the Veterinary Cooperative Oncology Group- Common Terminology Criteria for Adverse Events (VCOG-CTCAE) v1.1 guidelines. Viral shedding, neutralizing anti-reovirus antibody (NARA) production and immunohistochemical (IHC) detection of reovirus protein in the tumours were also assessed. AE was not observed in most dogs and events were limited to Grade I or II fever, vomiting, diarrhoea and inflammation of the injected tumour. No infectious virus was shed and all dogs had elevated NARA levels post-treatment. Although IHC results were only available in 6 dogs, 4 were detected positive for reovirus protein. In conclusion, reovirus is well-tolerated and can be given safely to tumour-bearing dogs according to the dosing regimen used in this study without significant concerns of viral shedding. Reovirus is also potentially effective in various types of canine tumours.

CXorf48 is a potential therapeutic target for achieving treatment-free remission in CML patients.

Although the introduction of tyrosine kinase inhibitors (TKIs) has improved overall survival of patients with chronic myeloid leukemia (CML), about half of the patients eventually relapse after cessation of TKIs. In contrast, the remainder of the patients maintain molecular remission without TKIs, indicating that the patients' immune system could control proliferation of TKI-resistant leukemic stem cells (LSCs). However, the precise mechanism of immunity against CML-LSCs is not fully understood. We have identified a novel immune target, CXorf48, expressed in LSCs of CML patients. Cytotoxic T cells (CTLs) induced by the epitope peptide derived from CXorf48 recognized CD34+CD38- cells obtained from the bone marrow of CML patients. We detected CXorf48-specific CTLs in the peripheral blood mononuclear cells from CML patients who have discontinued imatinib after maintaining complete molecular remission for more than 2 years. Significantly, the relapse rate of CXorf48-specific CTL-negative patients was 63.6%, compared to 0% in CXorf48-specific CTL-positive patients. These results indicate that CXorf48 could be a promising therapeutic target of LSCs for immunotherapy to obtain durable treatment-free remission in CML patients.

Skipping breakfast and 5-year changes in body mass index and waist circumference in Japanese men and women.

OBJECTIVE: This study investigated the relationship between frequency of skipping breakfast and annual changes in body mass index (BMI) and waist circumference (WC). METHODS: The participants were 4,430 factory employees. BMI and WC were measured repeatedly at annual medical examinations over a 5-year period. The association between frequency of skipping breakfast at the baseline examination and annual changes in anthropometric indices was evaluated using the generalized estimating equation method. RESULTS: The mean (standard deviation) BMI was 23.3 (3.0) kg m-2 for men and 21.9 (3.6) kg m-2 for women; and the mean WC was 82.6 (8.7) cm for men and 77.8 (9.8) cm for women. During the follow-up period, mean BMI increased by 0.2 kg m-2 for men and women, and mean WC increased by 1.1 cm for men and 1.0 cm for women. The annual change in the BMI of men who skipped breakfast four to six times per week was 0.061 kg m-2 higher, and that of those who skipped breakfast seven times per week was 0.046 kg m-2 higher, compared with those who did not skip breakfast. Annual changes in the WC of male participants who skipped breakfast seven times per week was 0.248 cm higher than that of those who did not skip breakfast. Skipping breakfast was not associated with changes in BMI or WC in women. CONCLUSIONS: Skipping breakfast was closely associated with annual changes in BMI and WC among men, and eating breakfast more than four times per week may prevent the excessive body weight gain associated with skipping breakfast.

Nosocomial BK Polyomavirus Infection Causing Hemorrhagic Cystitis Among Patients With Hematological Malignancies After Hematopoietic Stem Cell Transplantation.

BK polyomavirus (BKPyV) is recognized as a pathogen that causes diseases such as hemorrhagic cystitis and nephritis after allogeneic hematopoietic stem cell transplantation (HSCT) or renal transplantation. BKPyV-associated disease is thought to occur through reactivation under immunosuppression. However, the possibility of its nosocomial transmission and the clinical significance of such transmission have not been elucidated. During a 6-month period, nine adult patients (median age: 47 years) who had hematological disorders and who were treated with HSCT (n = 7) or chemotherapy (n = 2) in a single hematology department developed hemorrhagic cystitis due to BKPyV infection. The polymerase chain reaction products of BKPyV DNA obtained from each patient were sequenced. Of the nine patients, six had subtype I, 2 had subtype IV, and 1 had subtype II or III. In the alignment of sequences, four and two of the six subtype I strains were completely homologous (100%). These results strongly suggest that BKPyV has the potential to cause nosocomial infection within a medical facility, especially among recipients of HSCT. Further studies are clearly warranted to elucidate the route(s) of BKPyV transmission in order to establish optimal infection control.

Pathogenesis of Renal Lesions in Chickens After Experimental Infection With 9a5b Newcastle Disease Virus Mutant Isolate.

In this study, we investigated the pathogenesis of Newcastle disease virus (NDV) in the chicken kidney. Twenty-six 32-day-old specific pathogen-free chickens were intranasally inoculated with the 9a5b NDV mutant isolate. Kidney tissue samples, collected at 6 and 12 hours postinoculation (hpi) and 1, 2, 3, 5, and 10 days postinoculation (dpi), were analyzed by histopathology, immunohistochemistry (IHC), reverse transcription polymerase chain reaction (RT-PCR), and virus titration. Histopathologically, tubulointerstitial nephritis was detected in the renal cortex and predominantly in the medulla. Nephrotropism of 9a5b NDV was confirmed by IHC, RT-PCR, and virus isolation. Massive degenerative changes and infiltration of CD3-immunopositive cells accompanied replication of the 9a5b NDV isolate in chicken kidneys. In conclusion, pathological changes that were caused by NDV in chicken kidneys were similar to those caused by avian influenza virus, infectious bronchitis virus, and avian nephritis virus, and this highlights the importance of including NDV in the differential diagnosis of kidney disease in chickens.

Lip b 1 is a novel allergenic protein isolated from the booklouse, Liposcelis bostrychophila.

BACKGROUND: Booklice, belonging to the order Psocoptera, are small household insect pests that are distributed worldwide. Liposcelis bostrychophila, a common home-inhabiting species of booklouse, infests old books, sheets of paper, and stored food. Recent entomological and serological studies demonstrated that L. bostrychophila accounted for the majority of detectable insects in house dust and could be a potent inducer of respiratory allergy. Our recent proteomic analysis identified a potent allergenic protein from L. bostrychophila, designated Lip b 1, and determined its partial amino acid sequences. METHODS: Cloning of cDNAs for Lip b 1 was performed by large-scale transcriptome analysis (RNA-seq) and subsequent reverse transcription polymerase chain reaction. The full-length amino acid sequences deduced from Lip b 1 cDNAs were bioinformatically analyzed. The recombinant proteins of glutathione S-transferase (GST)-fused Lip b 1 were analyzed by Western blot and enzyme-linked immunosorbent assay. RESULTS: Lip b 1 cDNAs encoding two types of 254-amino acid proteins were cloned. The clones shared 87% identity, and the deduced molecular weights and isoelectric points were consistent with those determined in our previous study. The two types of Lip b 1 proteins in the GST-fused form were similarly reactive with sera from allergic patients sensitized with L. bostrychophila. CONCLUSIONS: Lip b 1 is a novel protein possibly causing booklouse allergy.

RUNX1 haploinsufficiency results in granulocyte colony-stimulating factor hypersensitivity.

RUNX1/AML1 is among the most commonly mutated genes in human leukemia. Haploinsufficiency of RUNX1 causes familial platelet disorder with predisposition to myeloid malignancies (FPD/MM). However, the molecular mechanism of FPD/MM remains unknown. Here we show that murine Runx1(+/-) hematopoietic cells are hypersensitive to granulocyte colony-stimulating factor (G-CSF), leading to enhanced expansion and mobilization of stem/progenitor cells and myeloid differentiation block. Upon G-CSF stimulation, Runx1(+/-) cells exhibited a more pronounced phosphorylation of STAT3 as compared with Runx1(+/+) cells, which may be due to reduced expression of Pias3, a key negative regulator of STAT3 signaling, and reduced physical sequestration of STAT3 by RUNX1. Most importantly, blood cells from a FPD patient with RUNX1 mutation exhibited similar G-CSF hypersensitivity. Taken together, Runx1 haploinsufficiency appears to predispose FPD patients to MM by expanding the pool of stem/progenitor cells and blocking myeloid differentiation in response to G-CSF.

Post-transplant lymphoproliferative disorder of the adrenal gland after allogeneic hematopoietic stem cell transplantation: report of two cases and literature review.

Post-transplant lymphoproliferative disorder (PTLD) is one of the life-threatening complications after hematopoietic stem cell transplantation (HSCT) and solid organ transplantation (SOT), and it is associated almost exclusively with Epstein-Barr virus (EBV). We herein report 2 cases of EBV-associated PTLD after allogeneic HSCT localized in the adrenal gland. Both patients developed adrenal tumor within 3 months after HSCT and were successfully treated with rituximab or tapering immunosuppressive agents. Both remained alive without recurrence. A literature review revealed 12 reported cases of PTLD involving the adrenal gland, but the adrenal gland was involved as one of the lesions of advanced-stage PTLD after SOT. To the best of our knowledge, this is the first report to show cases of isolated EBV-associated adrenal PTLD after HSCT. PTLD should be recognized as one of the causes of isolated adrenal tumor after HSCT.

Pathogenesis of Pancreatitis in Chickens after Experimental Infection with 9a5b Newcastle Disease Virus Mutant Isolate.

The aim of this study was to investigate the effect of Newcastle disease virus (NDV) on the chicken pancreas. A virulent 9a5b mutant NDV isolate was inoculated intranasally into 32-day-old specific pathogen-free white Leghorn chickens. The pancreas was examined grossly and fixed for histopathological, immunohistochemical and electron microscopical investigations. Inflammatory changes were observed in the peripancreatic tissue at the early stage of infection (12 h post infection) and became more prevalent towards the end of the experiment. Multifocal areas of necrotizing inflammation were detected in the exocrine portion of the pancreas by 5 days post infection (dpi) and became more severe at 10 dpi. The endocrine islets were generally preserved, but slight degenerative changes were observed at 10 dpi. Immunohistochemically, NDV-nucleoprotein (NDV-NP) signals were detected in the peripancreatic tissues (associated with macrophages and other lymphoid cells) by 1 dpi. In the exocrine portion of the pancreas, NDV-NP signals were detected at 5 dpi and increased in intensity and distribution by 10 dpi. NDV particles were confirmed in the cytoplasm of exocrine acinar cells by transmission electron microscopy. CD3-positive cells were observed in the peripancreatic tissues earlier than in the pancreatic tissue. Moreover, in comparison with control chickens, insulin immunoexpression was unchanged, except on the last day of the experiment, when it was slightly reduced. The 9a5b NDV infection induced an inflammatory reaction and viral replication in the peripancreatic tissues earlier than in the pancreatic tissue. Furthermore, necrosis affected mainly the exocrine portion of the pancreas, while the endocrine portion was generally unaffected.

Congenital multifocal increase of Purkinje fibres in a calf with cardiac conduction delay.

A female 4-month-old Holstein-Friesian calf was presented in heart failure. Microscopical examination of samples of the cardiac wall taken at necropsy examination revealed numerous aggregates of Purkinje fibres, particularly in the perivascular areas. Some Purkinje fibres were stained strongly with phosphotungstic acid haematoxylin and immunohistochemically were shown to express alpha smooth muscle actin, indicating an embryonic-like Purkinje fibre phenotype. A diagnosis of congenital multifocal increase of Purkinje fibres was made. The histological features of this case resemble multifocal cardiac Purkinje cell tumour of the heart in man.

Impaired hematopoietic differentiation of RUNX1-mutated induced pluripotent stem cells derived from FPD/AML patients.

Somatic mutation of RUNX1 is implicated in various hematological malignancies, including myelodysplastic syndrome and acute myeloid leukemia (AML), and previous studies using mouse models disclosed its critical roles in hematopoiesis. However, the role of RUNX1 in human hematopoiesis has never been tested in experimental settings. Familial platelet disorder (FPD)/AML is an autosomal dominant disorder caused by germline mutation of RUNX1, marked by thrombocytopenia and propensity to acute leukemia. To investigate the physiological function of RUNX1 in human hematopoiesis and pathophysiology of FPD/AML, we derived induced pluripotent stem cells (iPSCs) from three distinct FPD/AML pedigrees (FPD-iPSCs) and examined their defects in hematopoietic differentiation. By in vitro differentiation assays, FPD-iPSCs were clearly defective in the emergence of hematopoietic progenitors and differentiation of megakaryocytes, and overexpression of wild-type (WT)-RUNX1 reversed most of these phenotypes. We further demonstrated that overexpression of mutant-RUNX1 in WT-iPSCs did not recapitulate the phenotype of FPD-iPSCs, showing that the mutations were of loss-of-function type. Taken together, this study demonstrated that haploinsufficient RUNX1 allele imposed cell-intrinsic defects on hematopoietic differentiation in human experimental settings and revealed differential impacts of RUNX1 dosage on human and murine megakaryopoiesis. FPD-iPSCs will be a useful tool to investigate mutant RUNX1-mediated molecular processes in hematopoiesis and leukemogenesis.

Sugar-sweetened beverage and diet soda consumption and the 7-year risk for type 2 diabetes mellitus in middle-aged Japanese men.

PURPOSE: This cohort study investigated the association between sugar-sweetened beverage (SSB) and diet soda consumption and the incidence of type 2 diabetes in Japanese men. METHODS: The participants were 2,037 employees of a factory in Japan. We measured consumption of SSB and diet soda using a self-administered diet history questionnaire. The incidence of diabetes was determined in annual medical examinations over a 7-year period. Hazard ratios (HRs) with 95 % confidence intervals (CIs) for diabetes were estimated after adjusting for age, body mass index, family history, and dietary and other lifestyle factors. RESULTS: During the study, 170 participants developed diabetes. The crude incidence rates (/1,000 person-years) across participants who were rare/never SSB consumers, <1 serving/week, ≥ 1 serving/week and <1 serving/day, and ≥ 1 serving/day were 15.5, 12.7, 14.9, and 17.4, respectively. The multivariate-adjusted HR compared to rare/never SSB consumers was 1.35 (95 % CI 0.80-2.27) for participants who consumed ≥ 1 serving/day SSB. Diet soda consumption was significantly associated with the incident risk of diabetes (P for trend = 0.013), and multivariate-adjusted HRs compared to rare/never diet soda consumers were 1.05 (0.62-1.78) and 1.70 (1.13-2.55), respectively, for participants who consumed <1 serving/week and ≥ 1 serving/week. CONCLUSIONS: Consumption of diet soda was significantly associated with an increased risk for diabetes in Japanese men. Diet soda is not always effective at preventing type 2 diabetes even though it is a zero-calorie drink.

Loss of PTEN expression is an independent predictor of favourable survival in endometrial carcinomas.

BACKGROUND: We and others previously reported the prognostic significance of PTEN mutational status on favourable survival in endometrial carcinomas. Here, we demonstrate that loss of PTEN expression in immunohistochemistry is an independent prognostic marker for favourable survival in endometrial carcinomas. METHODS: We conducted immunohistochemical analyses of PTEN, PIK3CA, phosphorylated Akt (p-Akt), and p27 in primary endometrial carcinomas from 221 patients. Mutation of PTEN was analysed further. RESULTS: Expression of PTEN was lost in 56 patients (25%), and PIK3CA was overexpressed in 159 patients (72%). Overexpression of PIK3CA was associated with p-Akt overexpression (P<0.001), which was in turn associated with loss of nuclear p27 expression (P=0.028). Loss of PTEN expression was found to be associated with endometrioid histology (P=0.03), and was inversely associated with the presence of lymphovascular space invasion (P=0.03). Univariate and multivariate survival analyses revealed that factors of PTEN loss, age <70, histological grade 1, early International Federation of Gynecology and Obstetrics (FIGO) stage, and absence of lymphovascular invasion were independent prognostic indicators for better overall survival (P=0.03, 0.04, 0.01, <0.001, and 0.03, respectively). The subset analysis showed a stronger tendency of PTEN loss towards favourable survival in advanced-stage (III and IV) disease than in early-stage (I and II) disease (P=0.05 vs 0.14). Moreover, our mutational analysis demonstrated that PTEN expression loss was associated with PTEN-truncating mutations (P=0.03). CONCLUSION: The current observations further support the prognostic significance of PTEN aberration on favourable outcome in endometrial carcinomas, providing useful implications for the individualised management of the disease.