A new method of inducing selective brain hypothermia with saline perfusion into the subdural space: effects on transient cerebral ischemia in cats.

In this study, we tested brain surface cooling as a new method of inducing selective brain hypothermia, and evaluated its effects on focal cerebral ischemia using a cat model of transient middle cerebral artery (MCA) occlusion. Cats underwent 1 h of MCA occlusion followed by 5 h of reperfusion. Brain surface cooling was induced for 4 h during and after MCA occlusion in the hypothermia group, but not in the normothermia group. Brain surface cooling was performed using saline perfusion into the subdural space. Rectal temperature, brain surface temperature, and deep brain temperature were monitored, and regional cerebral blood flow (rCBF) and somatosensory evoked potential (SEP) were serially measured. After 5 h of reperfusion, water content was also measured. Although the rectal temperature was maintained at about 37 degrees C, the brain surface temperature decreased rapidly to 33 degrees C and was maintained at that temperature. For 3 h following reperfusion, the rCBF was lower in the hypothermia group than in the normothermia group. At 4 and 5 h after reperfusion, the recovery of SEP amplitude was significantly more enhanced in the hypothermia group than in the normothermia group. In the gray matter, the water content was significantly more diminished in the hypothermia group than in the normothermia group. These results demonstrate that our method is useful for protecting the ischemic brain from a transient MCA occlusion. This method may be adapted for neurological surgery.</p

Multiple pelvic insufficiency fractures in rheumatoid patients with mutilating changes

Multiple insufficiency fractures occurred in two patients with mutilating rheumatoid arthritis (RA), leading to substantial disabilities. Both patients received long-term oral glucocorticoid therapy and underwent multiple lower-extremity surgeries such as total hip arthroplasty (THA) or Total knee arthroplasty (TKA). The multiple fractures were located in the pelvis and lumbosacral region. Fractures in both patients were treated conservatively. Although bony union and resumption of activities were achieved in one patient, the other patient was not able to resume ambulation. For RA patients with combined risk factors for insufficiency fractures, aggressive preventive intervention and careful clinical assessment for early detection and management are warranted

Baikal mud volcanoes: thermal features of dynamic gas hydrate systems

In Lake Baikal shallow gas hydrates have already been identified in five mud volcano/seep structures through joint Russian, Japanese and Belgian research. These mud volcano/seep structures are found at different water depths (from 1380 m to as shallow as 440 m) and contain shallow hydrates of both structure I and II. Bottom Seismic Reflections (BSRs), indicative for the presence of deep-seated hydrates, has been observed on nearby seismic profiles. We will report on detailed thermal investigations in association with gravity coring performed over the last three years in the following gas hydrate containing mud volcanoes: “K-2”, “Malenkiy” and “Bolshoy”.The “K-2” mud volcano is located on the flanks of the Kukuy Canyon at a water depth of 900 m water depth. This oval structure of 60 m in height and 800 m in diameter consists of two separate mud volcanoes corresponding to two culminations. Sediment cores have been retrieved in more than 75 sites (15 contained hydrates), with temperature sensors attached to the corer in 22 occasions. Shallow hydrates were only found in two zones of not more 50-100 m diameter: on the top and between the two culminations. These zones also stand out by anomalous low (30-43 mK/m) and high (90-113 mK/m) thermal gradients in comparison to what is measured outside the mud volcano (60-70 mK/m). Cores with hydrates were directly correlated to low thermal gradient and large non-linearity in the temperature-depth profiles. This can be explained in three ways: (1) heat absorption by hydrate dissociation; (2) topographic effect combined with a dynamic hydrate system; and (3) infiltration of cold lake water, possibly induced by local convection and/or water segregation. The localized occurrence of hydrates within the mud volcanoes and a close relation to thermal anomalies was also observed in the mud volcanoes “Malenkiy” and “Bolshoy”, located at a water depth of about 1380m. More than 30 gravity cores in both structures indicate zones with shallow hydrates in local depressions and on culminations. Thermal stations show the presence of anomalous thermal gradients, up to 180 mK/m, at short distances of background values.The mud volcanoes in Lake Baikal do not display a strong activity in terms of acoustic flaring in the water column (almost absent) and large-scale temperature anomalies (< 1 °C). However, they comprise local shallow hydrate systems in close association with anomalous low and high thermal gradients. A dynamic nature of the hydrate system in “K-2” mud volcano has been supported by small shifts of the hydrate occurrence zone within the three year period of investigation

Mineralization of hydroxyapatite upon a unique xanthan gum hydrogel by an alternate soaking process

We previously reported a xanthan gum (Xan) hydrogel showing excellent mechanical properties. Mineralization of hydroxyapatite (Hap) upon the Xan hydrogel would provide a unique biomaterial applicable for bone tissue engineering. Here, we show the mineralization of Hap upon the Xan hydrogel by means of an alternate soaking process. Hap was gradually grown upon the Xan-matrix surface with increasing number of soaking cycles due to the ionic interactions between calcium cations and carboxyl groups. Interestingly, the mineralization induced a microstructure change in the gel-matrix from a layered structure to a porous structure. The mechanical properties of the resulting Hap–Xan composite hydrogels were further investigated by a tensile test, where the Hap–Xan composite hydrogel with an appropriate amount of Hap (Xan/Hap = 2.7) was capable of approximately 370% elongation

Physical properties of the Dome Fuji deep ice core (review)

Recent results of physical analyses of the Dome Fuji ice core are summarized with special attention to new methods introduced in the present studies. Microphysical processes which affect the ice core records are reviewed to better understand the paleoclimatic and paleoenvironmental signals stored

Hepatic Arterial Infusion Therapy with Cisplatin using Protein Binding Inhibition : Pharmacokinetics and Antineoplastic Effects of Cisplatin Combined with L-Cysteine in Rats

Cisplatin の蛋白結合には共有結合が関与しており、L-cysteine はcisplatin の共有結合を低下させる。そこで、この蛋白結合阻害を利用してcisplatin の肝動注療法の応用性について検討を行った。実験では、Donryu系雄性ラットにおけるL-cysteine 併用時におけるcisplatin の体内動態と抗腫瘍効果の影響について検討した。その結果、L-cysteine 併用においてcisplatin のtotal とfree 濃度に有意な差はみられなかった。また肝癌ラットを使用したin vivo 実験系において、L-cysteine を併用したcisplatin の肝動注はcisplatin のみの投与に比べ、腫瘍増殖率が抑えられる傾向であることを示した。さらに肝組織中における腫瘍部と非腫瘍部におけるcisplatin 濃度において、L-cysteine 併用により腫瘍部と非腫瘍部に有意な差を認めることができた (p<0.01)。以上の結果より、L-cysteine の併用はcisplatin の肝動注療法へ応用できると考えられる。Covalent binding is involved in the protein binding of cisplatin. L-cysteine reduces the covalent binding of cisplatin. We investigated hepatic arterial infusion therapy with cisplatin using protein binding inhibition. In the present experiment, the pharmacokinetics and antineoplastic effects of cisplatin combined with L-cysteine in male Donryu rats were investigated. As a result, no significant difference was noted in the total and free concentrations of cisplatin combined with L-cysteine. In an in vivo experiment using rats with liver cancer, the hepatic arterial infusion of cisplatin combined with L-cysteine showed that it was the tendency that tumor growth rate was inhibited in comparison with administration only for cisplatin. In addition, concentrations of cisplatin increased significantly between tumor and non-tumor regions in liver tissue when combined with L-cysteine (p<0.01). Thus, L-cysteine can be combined with cisplatin for hepatic arterial infusion therapy

Durvalumab Plus Carboplatin/Paclitaxel Followed by Maintenance Durvalumab With or Without Olaparib as First-Line Treatment for Advanced Endometrial Cancer: The Phase III DUO-E Trial

PURPOSE Immunotherapy and chemotherapy combinations have shown activity in endometrial cancer, with greater benefit in mismatch repair (MMR)-deficient (dMMR) than MMR-proficient (pMMR) disease. Adding a poly(ADP-ribose) polymerase inhibitor may improve outcomes, especially in pMMR disease. METHODS This phase III, global, double-blind, placebo-controlled trial randomly assigned eligible patients with newly diagnosed advanced or recurrent endometrial cancer 1:1:1 to: carboplatin/paclitaxel plus durvalumab placebo followed by placebo maintenance (control arm); carboplatin/paclitaxel plus durvalumab followed by maintenance durvalumab plus olaparib placebo (durvalumab arm); or carboplatin/paclitaxel plus durvalumab followed by maintenance durvalumab plus olaparib (durvalumab + olaparib arm). The primary end points were progression-free survival (PFS) in the durvalumab arm versus control and the durvalumab + olaparib arm versus control. RESULTS Seven hundred eighteen patients were randomly assigned. In the intention-to-treat population, statistically significant PFS benefit was observed in the durvalumab (hazard ratio [HR], 0.71 [95% CI, 0.57 to 0.89]; P = .003) and durvalumab + olaparib arms (HR, 0.55 [95% CI, 0.43 to 0.69]; P < .0001) versus control. Prespecified, exploratory subgroup analyses showed PFS benefit in dMMR (HR [durvalumab v control], 0.42 [95% CI, 0.22 to 0.80]; HR [durvalumab + olaparib v control], 0.41 [95% CI, 0.21 to 0.75]) and pMMR subgroups (HR [durvalumab v control], 0.77 [95% CI, 0.60 to 0.97]; HR [durvalumab + olaparib v control] 0.57; [95% CI, 0.44 to 0.73]); and in PD-L1-positive subgroups (HR [durvalumab v control], 0.63 [95% CI, 0.48 to 0.83]; HR [durvalumab + olaparib v control], 0.42 [95% CI, 0.31 to 0.57]). Interim overall survival results (maturity approximately 28%) were supportive of the primary outcomes (durvalumab v control: HR, 0.77 [95% CI, 0.56 to 1.07]; P = .120; durvalumab + olaparib v control: HR, 0.59 [95% CI, 0.42 to 0.83]; P = .003). The safety profiles of the experimental arms were generally consistent with individual agents. CONCLUSION Carboplatin/paclitaxel plus durvalumab followed by maintenance durvalumab with or without olaparib demonstrated a statistically significant and clinically meaningful PFS benefit in patients with advanced or recurrent endometrial cancer

The whole blood transcriptional regulation landscape in 465 COVID-19 infected samples from Japan COVID-19 Task Force

「コロナ制圧タスクフォース」COVID-19患者由来の血液細胞における遺伝子発現の網羅的解析 --重症度に応じた遺伝子発現の変化には、ヒトゲノム配列の個人差が影響する--. 京都大学プレスリリース. 2022-08-23.Coronavirus disease 2019 (COVID-19) is a recently-emerged infectious disease that has caused millions of deaths, where comprehensive understanding of disease mechanisms is still unestablished. In particular, studies of gene expression dynamics and regulation landscape in COVID-19 infected individuals are limited. Here, we report on a thorough analysis of whole blood RNA-seq data from 465 genotyped samples from the Japan COVID-19 Task Force, including 359 severe and 106 non-severe COVID-19 cases. We discover 1169 putative causal expression quantitative trait loci (eQTLs) including 34 possible colocalizations with biobank fine-mapping results of hematopoietic traits in a Japanese population, 1549 putative causal splice QTLs (sQTLs; e.g. two independent sQTLs at TOR1AIP1), as well as biologically interpretable trans-eQTL examples (e.g., REST and STING1), all fine-mapped at single variant resolution. We perform differential gene expression analysis to elucidate 198 genes with increased expression in severe COVID-19 cases and enriched for innate immune-related functions. Finally, we evaluate the limited but non-zero effect of COVID-19 phenotype on eQTL discovery, and highlight the presence of COVID-19 severity-interaction eQTLs (ieQTLs; e.g., CLEC4C and MYBL2). Our study provides a comprehensive catalog of whole blood regulatory variants in Japanese, as well as a reference for transcriptional landscapes in response to COVID-19 infection

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