Novel Heterogenous CHS1 Mutations Identified in Five Japanese Patients with Chediak-Higashi Syndrome

Chediak-Higashi syndrome (CHS) is a rare, autosomal recessive disorder characterized by oculocutaneous albinism, recurrent bacterial infections and progressive neurological dysfunction. We demonstrate novel heterogenous mutations of CHS1, the responsive gene of CHS, identified in five Japanese patients with CHS. Patients 1, 2, and 3 were siblings, and they had albinism of the skin and hair. They all had a heterogenous two-base deletion (c.5541-5542 del AA, p.Q1847fsX1850) in exon 18. Patient 4 had a heterogenous single-base insertion (c.3944-3945 ins C, p.T1315fsX1331) in exon 10. The patient exhibited severe early-onset phenotype and suffered from hemophagocytic lymphohistiocytosis. Patient 5 had two heterogenous nonsense mutations; c.7982C>G, p.S2661X in exon 30 and c.8281A>T, p.R2761X in exon 31. The patient suffered from infections in childhood and had visual disturbance and albinism of the skin and hair. The CHS1 mutations described here have not been reported previously

Frequent Consumption of Vegetables and The Decreased Risk of Ovarian Cancer

A case-control study was conducted to assess the relationship of dietary habits to ovarian cancer. A uniform questionnaire was filled out by 44 ovarian cancer cases hospitalized at Sapporo Medical University or 2 other hospitals in Sapporo between August and norember, 1990. Two hundred twenty individually locality-matched controls were selected from telephone books and sent the same questionnaire ; 156 (70.9%) responded. The conditional logistic regression anal-ysis was used to compare the data of 44 ovarian cancer cases and the 156 individ-ually age-matched controls. Univariate analysis revealed that single marital sta-tus was significantly associated with the increased risk of ovarian cancer (odds ratio, or OR=3.45, 95% confidence interval, or 95%CI 1.13-10.84). Frequent intake of midnight meals was also significantly related to the increased risk (trend, OR=1.56, 95%CI 1.01-2.41), and frequent intake of vegetables other than yellow or red was significantly related to the decreased risk (trend, OR= 0.58, 95%CI 0.37-0.91). These odds ratios concerning dietary habits were not substantially altered even after adjustment for potentially distorting variables such as marital status, the number of parities, and family history for uterine, ovarian, or breast cancer with the multivariate analysis. No other dietary habits, including frequent consumption of meat, fish, or milk, were associated with the increase or decrease of the risk of ovarian cancer

Association between preoperative toe perfusion index and maternal core temperature decrease during cesarean delivery under spinal anesthesia: a prospective cohort study

Background: The main mechanism of body temperature decrease during cesarean delivery under spinal anesthesia is core-to-peripheral redistribution of body heat, attributable to vasodilation. Perfusion index (PI) obtained with a pulse oximeter helps to assess peripheral perfusion dynamics by detecting the change in peripheral vascular tone. This study aimed to examine whether preoperative toe PI could predict the decrease in core temperature induced by spinal anesthesia during cesarean delivery.Methods: Parturients undergoing scheduled cesarean delivery under combined spinal-epidural anesthesia from September 2019 to March 2020 were enrolled in this single-center prospective cohort study. All parturients received 0.5% hyperbaric bupivacaine (10 mg) with fentanyl (15 μg) intrathecally. A pulse oximeter probe was placed on the left second toe for continuous PI measurement. The 3 M™ Bair Hugger™ Temperature Monitoring System placed over the right temporal region was used to record core temperature over time. We evaluated the association between the maximum core temperature decrease, which is the primary outcome, and the preoperative toe PI at operating room (OR) admission using a segmented regression model (SRM) and a generalized additive model (GAM). The maximum core temperature decrease was defined as the difference between core temperature at OR admission and minimum intraoperative core temperature.Results: Forty-eight patients were evaluated. In the SRM, the slope for the association between the maximum core temperature decrease and the preoperative toe PI changed from 0.031 to 0.124 after PI = 2.4%. Likewise, with the GAM, there was a small core temperature decrease when preoperative toe PI was greater than 2.0 to 3.0%.Conclusions: Low preoperative toe PI was associated with maternal core temperature decrease during cesarean delivery under spinal anesthesia. Preoperative toe PI is a simple, non-invasive, and effective tool for the early prediction of perioperative core temperature decrease during cesarean delivery.Trial registration: UMIN Clinical Trials Registry (registry number: UMIN000037965)

Insulin-like growth factor 1 modulates bioengineered tooth morphogenesis

Regenerative therapy to replace missing teeth is a critical area of research. Functional bioengineered teeth have been produced by the organ germ method using mouse tooth germ cells. However, these bioengineered teeth are significantly smaller in size and exhibit an abnormal crown shape when compared with natural teeth. The proper sizes and shapes of teeth contribute to their normal function. Therefore, a method is needed to control the morphology of bioengineered teeth. Here, we investigated whether insulin-like growth factor 1 (IGF1) can regulate the sizes and shapes of bioengineered teeth, and assessed underlying mechanisms of such regulation. IGF1 treatment significantly increased the size of bioengineered tooth germs, while preserving normal tooth histology. IGF1-treated bioengineered teeth, which were developed from bioengineered tooth germs in subrenal capsules and jawbones, showed increased sizes and cusp numbers. IGF1 increased the number of fibroblast growth factor (Fgf4)-expressing enamel knots in bioengineered tooth germs and enhanced the proliferation and differentiation of dental epithelial and mesenchymal cells. This study is the first to reveal that IGF1 increases the sizes and cusp numbers of bioengineered teeth via the induction of enamel knot formation, as well as the proliferation and differentiation of dental epithelial and mesenchymal cells

High Level Estradiol Induces EBV Reactivation and EBV gp350/220(+)CD138(+) Double-positive B Cell Population in Graves’ Disease Patients and Healthy Controls

Graves’ disease occurs predominantly in women. Epstein-Barr virus (EBV) mainly persists in human B lymphocytes, and its reactivation stimulates antibody production. We previously suggested that the EBV reactivation-induced production of TRAb and IgM at 100 nM estradiol (pregnant level) was lower than that at 0 nM estradiol and that class switch recombination may be increased by estradiol. In this study, we examined the effect of estradiol on EBV reactivation. We identified the expression of EBV-glycoprotein 350/220 (gp350/220) in the late phase of reactivation and plasma cell differentiation of EBV-infected cells using 72A1 antibody and CD138 antibody, respectively. We found the mean ratio of gp 350/220(+) CD138(+) cells at 100 nM estradiol was higher than that at 0 nM estradiol. These results suggested that EBV-infected cells could survive with keeping the ability of antibody production in 100 nM estradiol, which is consistent with the improvement of Graves’ disease during maternity and exacerbation postpartum

Characterisation of Ppy-lineage cells clarifies the functional heterogeneity of pancreatic beta cells in mice

Aims/hypothesis Pancreatic polypeptide (PP) cells, which secrete PP (encoded by the Ppy gene), are a minor population of pancreatic endocrine cells. Although it has been reported that the loss of beta cell identity might be associated with beta-to-PP cell-fate conversion, at present, little is known regarding the characteristics of Ppy-lineage cells. Methods We used Ppy-Cre driver mice and a PP-specific monoclonal antibody to investigate the association between Ppy-lineage cells and beta cells. The molecular profiles of endocrine cells were investigated by single-cell transcriptome analysis and the glucose responsiveness of beta cells was assessed by Ca2+ imaging. Diabetic conditions were experimentally induced in mice by either streptozotocin or diphtheria toxin. Results Ppy-lineage cells were found to contribute to the four major types of endocrine cells, including beta cells. Ppy-lineage beta cells are a minor subpopulation, accounting for 12–15% of total beta cells, and are mostly (81.2%) localised at the islet periphery. Unbiased single-cell analysis with a Ppy-lineage tracer demonstrated that beta cells are composed of seven clusters, which are categorised into two groups (i.e. Ppy-lineage and non-Ppy-lineage beta cells). These subpopulations of beta cells demonstrated distinct characteristics regarding their functionality and gene expression profiles. Ppy-lineage beta cells had a reduced glucose-stimulated Ca2+ signalling response and were increased in number in experimental diabetes models. Conclusions/interpretation Our results indicate that an unexpected degree of beta cell heterogeneity is defined by Ppy gene activation, providing valuable insight into the homeostatic regulation of pancreatic islets and future therapeutic strategies against diabetes

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ヒト胎盤およびブタ水晶体と筋肉から精製したアルドース還元酵素に及ぼす加水分解型および縮合型タンニンの阻害を比較した。ガロタンニンは他のタンニンより強くこれらの酵素を阻害し, このうち1,2,3,4,6-penta-O-galloyl-β-D-glucose(PGG)が最も低いIC_値(60-70nM)を示した。PGGはアルコール脱水素酵素, アルデヒド還元酵素, カルボニル還元酵素に対して低度の阻害しか示さなかった。PGGによるアルドース還元酵素の阻害様式はカルボニル基質に対して混合型であったが, 活性化剤である硫酸イオン存在下では不拮抗型となった。The inhibitory effects of various hydrolyzable and condensed tannins for aldose reductases of human placenta, pig lens and pig muscle were examined and compared. Gallotannins inhibited these enzymes much more than other tannins with 1,2,3,4,6-penta-O-galloyl-β-D-glucose (PGG) showing the lowest IC_ values (60-70 nM). PGG had low inhibitory effect on aldehyde reductase, carbonyl reductase and alcohol dehydrogenase. The inhibition of aldose reductase by PGG was of the mixed type with respect to the carbonyl substrate, but the inhibition was found to be uncompetitive when assaying enzyme activity in the presence of sulfate ions, an activator of the enzyme

Selective depletion of mouse kidney proximal straight tubule cells causes acute kidney injury

The proximal straight tubule (S3 segment) of the kidney is highly susceptible to ischemia and toxic insults but has a remarkable capacity to repair its structure and function. In response to such injuries, complex processes take place to regenerate the epithelial cells of the S3 segment; however, the precise molecular mechanisms of this regeneration are still being investigated. By applying the “toxin receptor mediated cell knockout” method under the control of the S3 segment-specific promoter/enhancer, Gsl5, which drives core 2 β-1,6-N-acetylglucosaminyltransferase gene expression, we established a transgenic mouse line expressing the human diphtheria toxin (DT) receptor only in the S3 segment. The administration of DT to these transgenic mice caused the selective ablation of S3 segment cells in a dose-dependent manner, and transgenic mice exhibited polyuria containing serum albumin and subsequently developed oliguria. An increase in the concentration of blood urea nitrogen was also observed, and the peak BUN levels occurred 3–7 days after DT administration. Histological analysis revealed that the most severe injury occurred in the S3 segments of the proximal tubule, in which tubular cells were exfoliated into the tubular lumen. In addition, aquaporin 7, which is localized exclusively to the S3 segment, was diminished. These results indicate that this transgenic mouse can suffer acute kidney injury (AKI) caused by S3 segment-specific damage after DT administration. This transgenic line offers an excellent model to uncover the mechanisms of AKI and its rapid recovery