Endoplasmic Reticulum Stress-Related Inflammation and Cardiovascular Diseases

The endoplasmic reticulum (ER) is the site of synthesis and maturation of proteins designed for secretion or for localization on the cell membrane. Various types of stress from both inside and outside cells disturb ER function, thus causing unfolded or misfolded proteins to accumulate in the ER. To improve and maintain the ER functions against such stresses, the ER stress response pathway is activated. However, when the stress is prolonged or severe, apoptosis pathways are activated to remove damaged cells. It was recently reported that the ER stress pathway is also involved in the inflammatory response, whereby inflammation induces ER stress, and ER stress induces an inflammatory response. Therefore, the ER stress response pathway is involved in various diseases, including cardiovascular diseases such as atherosclerosis and ischemic diseases, in various ways. The ER stress pathway may represent a novel target for the treatment of these diseases

Bilateral Pneumothorax Associated With Lung and Pleural Metastases of Breast Cancer

A rare case of bilateral pneumothorax in a 54-year-old woman with advanced breast cancer associated with lung and pleural metastases is presented. The patient was admitted to our hospital complaining of unexpected severe dyspnea. A chest X-ray showed bilateral pneumothorax associated with multiple lung metastases and pleural effusions, followed by immediate pleural drainage. Although air leak and effusions of the right lung were well controlled by the conservative management, massive air leaks of the left lung had continued for 40 days. Because of patient's poor general status a surgical closure of the leaking site was selected using video-assisted thoracoscopic surgery techniques. Thoracoscopy revealed a ruptured bulla in the lower lobe (S6), thus, followed by a successful bullectomy with a stapling device. We speculate that multiple pleural metastasis may disturb the normal repair mechanism of the lung tissue and cause prolonged persistent air leaks

Skeletal FGFR1 signaling is necessary for regulation of serum phosphate level by FGF23 and normal life span

Fibroblast growth factor (FGF) 23 produced by the bone is the principal hormone to regulate serum phosphate level. Serum FGF23 needs to be tightly regulated to maintain serum phosphate in a narrow range. Thus, we hypothesized that the bone has some phosphate-sensing mechanism to regulate the production of FGF23. Previously we showed that extracellular phosphate induces the phosphorylation of FGF receptor 1 (FGFR1) and FGFR1 signaling regulates the expression of Galnt3, whose product works to increase FGF23 production in vitro. In this study, we show the significance of FGFR1 in the regulated FGF23 production and serum phosphate level in vivo. We generated late-osteoblast/osteocyte-specific Fgfr1-knockout mice (Fgfr1fl/fl; OcnCre/+) by crossing the Ocn-Cre and the floxed Fgfr1 mouse lines. We evaluated serum phosphate and FGF23 levels, the expression of Galnt3 in the bone, the body weight and life span. A selective ablation of Fgfr1 aborted the increase of serum active full-length FGF23 and the enhanced expression of Galnt3 in the bone by a high phosphate diet. These mice showed more pronounced hyperphosphatemia compared with control mice. In addition, these mice fed with a control diet showed body weight loss after 23 weeks of age and shorter life span. These results reveal a novel significance of FGFR1 signaling in the phosphate metabolism and normal life span

Relationship between serum calcium or phosphate levels and mortality stratified by parathyroid hormone level: an analysis from the MBD-5D study

Introduction: There is limited evidence about the association between calcium and phosphate levels and mortality stratified by intact parathyroid hormone (iPTH) level. Methods: We investigated whether differences in iPTH level affect the relationship between calcium and phosphate levels and all-cause mortality in hemodialysis patients with secondary hyperparathyroidism (SHPT). Calcium and phosphate levels were categorized as low (< 8.5 mg/dL,  < 4.0 mg/dL), medium (≥ 8.5–< 9.5 mg/dL,  ≥ 4.0–< 7.0 mg/dL), and high (≥ 9.5 mg/dL,  ≥ 7.0 mg/dL), respectively. iPTH levels were grouped into < 300 or ≥ 300 pg/mL. Adjusted incidence rate ratios (aIRRs) were analyzed by weighted Poisson regression. Results: For calcium, patients with higher iPTH (≥ 300 pg/mL) had significantly higher all-cause mortality rates in the high than in the medium category (aIRR 1.99, 95% confidence interval [CI] 1.16–3.42), and tended to have a higher mortality rate in the low category (aIRR 2.04, 95% CI 0.94–4.42). Patients with lower iPTH (< 300 pg/mL) had higher mortality rates in the high than in the medium category (aIRR 1.65, 95% CI 1.39–1.96). For phosphate, the mortality rate was significantly higher in the high than in the medium category in patients with higher and lower iPTH (aIRR 3.23, 95% CI 1.63–6.39 for iPTH ≥ 300 pg/mL; aIRR 1.58, 95% CI 1.06–2.36 for iPTH < 300 pg/mL). Conclusion: High calcium and phosphate levels were associated with increased risk of mortality irrespective of iPTH level

The Interaction Pattern of Murine Serum Ficolin-A with Microorganisms

The ficolins are soluble pattern recognition molecules in the lectin pathway of complement, but the spectrum and mode of interaction with pathogens are largely unknown. In this study, we investigated the binding properties of the murine serum ficolin-A towards a panel of different clinical relevant microorganisms (N = 45) and compared the binding profile with human serum ficolin-2 and ficolin-3. Ficolin-A was able to bind Gram-positive bacteria strains including E. faecalis, L. monocytogenes and some S. aureus strains, but not to the investigated S. agalactiae (Group B streptococcus) strains. Regarding Gram-negative bacteria ficolin-A was able to bind to some E. coli and P. aeruginosa strains, but not to the investigated Salmonella strains. Of particular interest ficolin-A bound strongly to the pathogenic E. coli, O157:H7 and O149 strains, but it did not bind to the non-pathogenic E. coli, ATCC 25922 strain. Additionally, ficolin-A was able to bind purified LPS from these pathogenic strains. Furthermore, ficolin-A bound to a clinical isolate of the fungus A. fumigatus. In general ficolin-2 showed similar selective binding spectrum towards pathogenic microorganisms as observed for ficolin-A indicating specific pathophysiological roles of these molecules in host defence. In contrast, ficolin-3 did not bind to any of the investigated microorganisms and the anti-microbial role of ficolin-3 still remains elusive

<Orignal>The Relationship Between the Pharmacological Effects of Benzodiazepines and Their in vivo Binding Sites in the Brain of Rats.

ベンゾジアゼピン系薬剤とフェノバルビタール薬理作用と脳内分布との関連を生体内で調べるため, 60匹のラット(体重470～480 g)を3郡に分け, 3^H-diazepam, 3^H-flunitrazepamまたは3^H-ohenobarbital 5μciを投与した。それぞれのグループのラットは薬剤の静脈内投与後3分, 10分, または40分の時点で断頭し, 各組織の放射能を測定し, d.p.m/g・tissueに換算した。この結果, 3^H-diazepamの放射線量は脳幹および視床下部で他の大脳皮質に比べ有意に高かった。また, 3^H-phenobarbitalの脳内濃度は換与後40分経ってもほとんど低下しなかった。これらの結果はベンゾジアゼピン系薬剤の薬理作用との密接な関連があり, in-vitroで証明されたbenzobiazepinereceotorはin-vivoではあまり重要な意味を持たない可能性があることを示唆している。To compare the in vitro pharmacological effect and in the brain distribution of benzodiazepines and phenobarbital, three group of sixty anesthetized rats (470～480g) were administered 5μCi of 3^H-diazepam, 3^H-flunitrazepam or 3^H-phenobarbital. The rats were decapitated 3, 10, or 40 minutes after the intravenous injection of these drugs. Radioactivity of the tissue was measured and calculated as d.p.m./g. tissue. 3^H-diazepam radioactivity in the brainstem and hypothalamus was significantly higher than in the brain cortex 3 and 10 minutes after the injection. 3^H-flunitrazepam radioactivity in the brain cortex was higher than in other regions. There was no significant decrease in 3^H-phenobarbital brain concentration, even 40 minutes after injection. The distribution of benzodiazepine is closely related with its pharmacological effect, and this suggests that in vitro benzodiazepine binding sites are not responsible for the pharmacological action in vivo

Reconsideration of Laparoscopic Cholecystectomy

We describe the surgical method of cases showing a distended gallbladder. Because the most important thing does not cause biliary tract injury, it is to find orientation carefully. The frequency of incidental gallbladder cancer was in 7 (0.7%) of the 983. Only cholecystectomy is necessary to be performed for Tis or T1 cancer, and surgery has to be changed to radical surgery for T2 cancer or deeper invasion. Laparoscopic cholecystectomy is already an established standard operation. In the presence of acute or severe chronic inflammation, special attention should be paid to these points

Congenital insensitivity to pain with anhidrosis (CIPA): effect of TRKA (NTRK1) missense mutations on autophosphorylation of the receptor tyrosine kinase for nerve growth factor

Human TRKA (NTRK1) encodes the receptor tyrosine kinases (RTKs) for nerve growth factor (NGF) and is the gene responsible for congenital insensitivity to pain with anhidrosis (CIPA), an autosomal recessive disorder characterized by a lack of pain sensation and anhidrosis. We reported 11 putative missense mutations in 31 CIPA families from various ethnic groups. Here we have introduced the corresponding mutations into the TRKA cDNA and examined NGF-stimulated autophosphorylation. We find that wild-type TRKA precursor proteins in a neuronal and a non-neuronal cell line were differentially processed and phosphorylated in an NGF-dependent and -independent manner, respectively. Two mutants (L93P and L213P) in the extracellular domain were aberrantly processed and showed diminished autophosphorylation in neuronal cells. Five mutants (G516R, G571R, R643W, R648C and G708S) in the tyrosine kinase domain were processed as wild-type TRKA but showed significantly diminished auto-phosphorylation in both neuronal and non-neuronal cells. In contrast, R85S and (H598Y; G607V), detected previously as double and triple mutations, are probably polymorphisms in a particular ethnic background. The other putative mutant D668Y might be a rare polymorphism or might impair the function of TRKA without compromising autophosphorylation. Mutated residues in the tyrosine kinase domain are conserved in various RTKs and probably contribute to critical function of these proteins. Thus, naturally occurring TRKA missense mutations with loss of function provide considerable insight into the structure-function relationship in the RTK family. Our data may aid in developing a drug which targets the clinically devastating \u27complex regional pain syndrome\u27