CFTR gene mutations in Japanese individuals with congenital bilateral absence of the vas deferens

AbstractCongenital bilateral absence of the vas deferens (CBAVD) is a monosymptomatic disease confined to the male reproductive system with similarity to the phenotype of cystic fibrosis (CF), and mutations in the CFTR gene are highly prevalent in Caucasian CBAVD patients. While CF is very rare in Japan, CBAVD is not. Our previous study demonstrated high prevalence of the 5T allele in the CFTR gene in Japanese CBAVD patients. We analyzed whole exons of the CFTR gene in 19 CBAVD patients and 53 normal individuals using polymerase chain reaction amplification-single strand conformation polymorphism analysis and direct sequencing. Three missense mutations (W216X, G1349S, Q1352H) were found in seven CFTR alleles, and the 5T allele was positive in 11 of 38 CFTR patient alleles. Consequently, 47% of CFTR chromosomes in the patients were affected, and 11 individuals (58%) had at least one mutated CFTR allele. In contrast, three of 53 normal individuals (5.7%) had a missense mutation in one of the CFTR genes, but no 5T allele was detected (both P<0.0001). Mutations of the CFTR gene are closely associated with Japanese patients with CBAVD

Acute Polyradiculoneuropathy Associated With Salmonella Gastroenteritis

We reported a case of acute polyradiculoneuropathy associated with Salmonella gastroenteritis. A68-year-oldman developed progressive motor weakness and areflexia following the febrile illness and diarrhea caused by a strain of Salmonella species O8 group. He showed a rapid and complete recovery from the illness. This is the first report in which Salmonella gastroenteritis might be etiologically related to an acute polyradiculoneuropathy

Antiphospholipid Antibodies in Patients with Myasthenia Gravis

We measured antiphospholipid antibodies in sera from 94 patients with myasthenia gravis (MG). We found lgG aCL in 14/94 (14.9 % )lgM aCL in 6/94 (6.4 %) and LA in 4/56 (7.1 %) patients with MG. As a whole 21 of 94 (22.3 % ) patients with MG had some aPL. There was no correlation between the presence of aPL and the severity of MGthe presence of hyperplasia of thymustiter of the antiacetylcholine receptor antibodies or anti-single stranded DNA antibodies. Though the percentage of malignant thymoma with aPL were higher than that of malignant thymoma without aPLwe thought that aPL were not the specific antibody in malignant thymoma. In MGaPL did not play as the aCL syndrome and seemed to be non-specific antibodies

ALCHEMI Finds a “Shocking” Carbon Footprint in the Starburst Galaxy NGC 253

The centers of starburst galaxies may be characterized by a specific gas and ice chemistry due to their gas dynamics and the presence of various ice desorption mechanisms. This may result in a peculiar observable composition. We analyse the abundances of CO2, a reliable tracer of ice chemistry, from data collected as part of the Atacama Large Millimeter/submillimeter Array large program ALCHEMI, a wide-frequency spectral scan toward the starburst galaxy NGC 253 with an angular resolution of 1.″6. We constrain the CO2 abundances in the gas phase using its protonated form HOCO+. The distribution of HOCO+ is similar to that of methanol, which suggests that HOCO+ is indeed produced from the protonation of CO2 sublimated from ice. The HOCO+ fractional abundances are found to be (1-2) 7 10−9 at the outer part of the central molecular zone (CMZ), while they are lower (∼10−10) near the kinematic center. This peak fractional abundance at the outer CMZ is comparable to that in the Milky Way CMZ, and orders of magnitude higher than that in Galactic disk, star-forming regions. From the range of HOCO+/CO2 ratios suggested from chemical models, the gas-phase CO2 fractional abundance is estimated to be (1-20) 7 10−7 at the outer CMZ, and orders of magnitude lower near the center. We estimate the CO2 ice fractional abundances at the outer CMZ to be (2-5) 7 10−6 from the literature. A comparison between the ice and gas CO2 abundances suggests an efficient sublimation mechanism. This sublimation is attributed to large-scale shocks at the orbital intersections of the bar and CMZ

SLPI is a critical mediator that controls PTH-induced bone formation

Osteoclastic bone resorption and osteoblastic bone formation/replenishment are closely coupled in bone metabolism. Anabolic parathyroid hormone (PTH), which is commonly used for treating osteoporosis, shifts the balance from osteoclastic to osteoblastic, although it is unclear how these cells are coordinately regulated by PTH. Here, we identify a serine protease inhibitor, secretory leukocyte protease inhibitor (SLPI), as a critical mediator that is involved in the PTH-mediated shift to the osteoblastic phase. Slpi is highly upregulated in osteoblasts by PTH, while genetic ablation of Slpi severely impairs PTH-induced bone formation. Slpi induction in osteoblasts enhances its differentiation, and increases osteoblast–osteoclast contact, thereby suppressing osteoclastic function. Intravital bone imaging reveals that the PTH-mediated association between osteoblasts and osteoclasts is disrupted in the absence of SLPI. Collectively, these results demonstrate that SLPI regulates the communication between osteoblasts and osteoclasts to promote PTH-induced bone anabolism.Morimoto A., Kikuta J., Nishikawa K., et al. SLPI is a critical mediator that controls PTH-induced bone formation. Nature Communications 12, 2136 (2021); https://doi.org/10.1038/s41467-021-22402-x

Energizing Star Formation: The Cosmic Ray Ionization Rate in NGC 253 Derived From ALCHEMI Measurements of H3_3O+^+ and SO

The cosmic ray ionization rate (CRIR) is a key parameter in understanding the physical and chemical processes in the interstellar medium. Cosmic rays are a significant source of energy in star formation regions, which impacts the physical and chemical processes which drive the formation of stars. Previous studies of the circum-molecular zone (CMZ) of the starburst galaxy NGC 253 have found evidence for a high CRIR value; $10^3-10^6$ times the average cosmic ray ionization rate within the Milky Way. This is a broad constraint and one goal of this study is to determine this value with much higher precision. We exploit ALMA observations towards the central molecular zone of NGC 253 to measure the CRIR. We first demonstrate that the abundance ratio of H$_3$O$^+$ and SO is strongly sensitive to the CRIR. We then combine chemical and radiative transfer models with nested sampling to infer the gas properties and CRIR of several star-forming regions in NGC 253 due to emission from their transitions. We find that each of the four regions modelled has a CRIR in the range $(1-80)\times10^{-14}$ s$^{-1}$ and that this result adequately fits the abundances of other species that are believed to be sensitive to cosmic rays including C$_2$H, HCO$^+$, HOC$^+$, and CO. From shock and PDR/XDR models, we further find that neither UV/X-ray driven nor shock dominated chemistry are a viable single alternative as none of these processes can adequately fit the abundances of all of these species.Comment: 24 pages, 15 figures, accepted for publication in Ap

Tracing Interstellar Heating: An ALCHEMI Measurement of the HCN Isomers in NGC 253

We analyze HCN and HNC emission in the nearby starburst galaxy NGC 253 to investigate its effectiveness in tracing heating processes associated with star formation. This study uses multiple HCN and HNC rotational transitions observed using the Atacama Large Millimeter/submillimeter Array via the ALCHEMI Large Program. To understand the conditions and associated heating mechanisms within NGC 253\u27s dense gas, we employ Bayesian nested sampling techniques applied to chemical and radiative transfer models, which are constrained using our HCN and HNC measurements. We find that the volume density n H 2 and cosmic-ray ionization rate (CRIR) ζ are enhanced by about an order of magnitude in the galaxy’s central regions as compared to those further from the nucleus. In NGC 253\u27s central giant molecular clouds (GMCs), where observed HCN/HNC abundance ratios are the lowest, n ∼ 105.5 cm−3 and ζ ∼ 10−12 s−1 (greater than 104 times the average Galactic rate). We find a positive correlation in the association of both density and CRIR with the number of star formation-related heating sources (supernova remnants, H ii regions, and super hot cores) located in each GMC, as well as a correlation between CRIRs and supernova rates. Additionally, we see an anticorrelation between the HCN/HNC ratio and CRIR, indicating that this ratio will be lower in regions where ζ is higher. Though previous studies suggested HCN and HNC may reveal strong mechanical heating processes in NGC 253\u27s CMZ, we find cosmic-ray heating dominates the heating budget, and mechanical heating does not play a significant role in the HCN and HNC chemistry

Detection of Epstein-Barr Virus and Helicobacter pylori in Primary Malignant Gastric Lymphomas

We studied five patients diagnosed with primary gastric lymphoma between 1985 and 1995 in Omura Munisipa Hospital to investigate the relationship between Helicobacter pylori, Epstein-Barr virus and primary malignant gastric lymphoma. H. pylori was detected by hematoxylin-eosin stain, Giemsa stain, immunohistochemistry while EBV was detected by in situ hybridization in the lymphoma and background mucosa. H. pylori but not EBV, was detected in all cases. Furthermore, malignant lymphomas were mainly located in the area of the fundic gland where H. pylori was frequently identified and caused inflammation. In contrast, malignant lymphomas were not detected in areas with intestinal metaplasia. Our results suggest that malignant lymphoma may develop in a region where the immune system has been activated by H. pylori. In contrast, EBV is unlikely to play an important role in the development of gastric lymphoma, compared to H. pylori

DOCK2 is involved in the host genetics and biology of severe COVID-19

「コロナ制圧タスクフォース」COVID-19疾患感受性遺伝子DOCK2の重症化機序を解明 --アジア最大のバイオレポジトリーでCOVID-19の治療標的を発見--. 京都大学プレスリリース. 2022-08-10.Identifying the host genetic factors underlying severe COVID-19 is an emerging challenge. Here we conducted a genome-wide association study (GWAS) involving 2, 393 cases of COVID-19 in a cohort of Japanese individuals collected during the initial waves of the pandemic, with 3, 289 unaffected controls. We identified a variant on chromosome 5 at 5q35 (rs60200309-A), close to the dedicator of cytokinesis 2 gene (DOCK2), which was associated with severe COVID-19 in patients less than 65 years of age. This risk allele was prevalent in East Asian individuals but rare in Europeans, highlighting the value of genome-wide association studies in non-European populations. RNA-sequencing analysis of 473 bulk peripheral blood samples identified decreased expression of DOCK2 associated with the risk allele in these younger patients. DOCK2 expression was suppressed in patients with severe cases of COVID-19. Single-cell RNA-sequencing analysis (n = 61 individuals) identified cell-type-specific downregulation of DOCK2 and a COVID-19-specific decreasing effect of the risk allele on DOCK2 expression in non-classical monocytes. Immunohistochemistry of lung specimens from patients with severe COVID-19 pneumonia showed suppressed DOCK2 expression. Moreover, inhibition of DOCK2 function with CPYPP increased the severity of pneumonia in a Syrian hamster model of SARS-CoV-2 infection, characterized by weight loss, lung oedema, enhanced viral loads, impaired macrophage recruitment and dysregulated type I interferon responses. We conclude that DOCK2 has an important role in the host immune response to SARS-CoV-2 infection and the development of severe COVID-19, and could be further explored as a potential biomarker and/or therapeutic target

Why Are Outcomes Different for Registry Patients Enrolled Prospectively and Retrospectively? Insights from the Global Anticoagulant Registry in the FIELD-Atrial Fibrillation (GARFIELD-AF).

Background: Retrospective and prospective observational studies are designed to reflect real-world evidence on clinical practice, but can yield conflicting results. The GARFIELD-AF Registry includes both methods of enrolment and allows analysis of differences in patient characteristics and outcomes that may result. Methods and Results: Patients with atrial fibrillation (AF) and ≥1 risk factor for stroke at diagnosis of AF were recruited either retrospectively (n = 5069) or prospectively (n = 5501) from 19 countries and then followed prospectively. The retrospectively enrolled cohort comprised patients with established AF (for a least 6, and up to 24 months before enrolment), who were identified retrospectively (and baseline and partial follow-up data were collected from the emedical records) and then followed prospectively between 0-18 months (such that the total time of follow-up was 24 months; data collection Dec-2009 and Oct-2010). In the prospectively enrolled cohort, patients with newly diagnosed AF (≤6 weeks after diagnosis) were recruited between Mar-2010 and Oct-2011 and were followed for 24 months after enrolment. Differences between the cohorts were observed in clinical characteristics, including type of AF, stroke prevention strategies, and event rates. More patients in the retrospectively identified cohort received vitamin K antagonists (62.1% vs. 53.2%) and fewer received non-vitamin K oral anticoagulants (1.8% vs . 4.2%). All-cause mortality rates per 100 person-years during the prospective follow-up (starting the first study visit up to 1 year) were significantly lower in the retrospective than prospectively identified cohort (3.04 [95% CI 2.51 to 3.67] vs . 4.05 [95% CI 3.53 to 4.63]; p = 0.016). Conclusions: Interpretations of data from registries that aim to evaluate the characteristics and outcomes of patients with AF must take account of differences in registry design and the impact of recall bias and survivorship bias that is incurred with retrospective enrolment. Clinical Trial Registration: - URL: http://www.clinicaltrials.gov . Unique identifier for GARFIELD-AF (NCT01090362)