Hepatic steatosis rather than visceral adiposity is more closely associated with insulin resistance in the early stage of obesity

The aim of the present study was to investigate the specific relationship between hepatic steatosis and insulin resistance in the early stage of obesity. Among general health examinees who received an ultrasound scanning, 131 subjects without fatty liver (non-FL group) and 142 subjects with fatty liver (FL group) were selected so that both groups were matched for age, sex, body mass index, and % body fat. The FL group was then subdivided into 2 groups according to the severity of steatosis by ultrasound. Insulin resistance was assessed by homeostasis model assessment for insulin resistance, serum high-molecular-weight (HMW) adiponectin, and insulin-like growth factor binding protein 1 concentrations. Unexpectedly, the non-FL group showed higher waist circumference than the FL group. Nevertheless, homeostasis model assessment for insulin resistance as well as conventional insulin resistance indexes such as serum insulin, free fatty acid, and triglyceride levels demonstrated a stepwise increase, and HMW adiponectin and insulin-like growth factor binding protein 1 demonstrated a stepwise decrease with increasing degree of hepatic steatosis. Overall, insulin resistance markers correlated with obesity indexes, but only HMW adiponectin no longer showed any meaningful correlation in the presence of fatty liver. The prevalence of BP, fasting serum glucose, and high-density lipoprotein cholesterol above or below cutoff points and subjects having 2 or more metabolic syndrome components were higher in the moderate to severe FL group compared to the non-FL group. In conclusion, these results in nondiabetic and relatively normal-body mass index subjects suggest that hepatic steatosis is independently associated with insulin resistance regardless of extrahepatic adiposity and might be the earliest event in pathogenesis of the metabolic syndrome.     

Characterization of a mammalian mutant with a camptothecin-resistant DNA topoisomerase I.

DNA topoisomerase I was purified to near homogeneity from a clonal line of human lymphoblastic leukemia cells, RPMI 8402, that is resistant to camptothecin, a cytotoxic alkaloid from Camptotheca acuminata, and compared with that of the parent wild-type cells. As assayed by relaxation of the supercoiled plasmid DNA and by formation of enzyme-linked DNA breaks, the purified enzyme from the resistant cells was shown to be greater than 125-fold as resistant to camptothecin as the wild-type enzyme, comparable to a cellular resistance index of about 300. Therefore, the cellular resistance appears to be due to the resistance of the enzyme. The amount of the immunoreactive enzyme protein in whole extract appeared to be reduced to less than half that of the wild-type enzyme. These results establish that DNA topoisomerase I is the cellular target of camptothecin and that DNA topoisomerase I is essential for the survival of mammalian cells.     

Venous tumor thrombosis and cavernous transformation of the portal vein in a patient with gastric carcinoma

A case of extensive extra-and intrahepatic portal tumor thrombosis, with no metastatic foci in liver parenchyma, secondary to advanced gastric carcinoma in a 69-year-old man is reported. The portal tumor thrombosis was characterized by enlargement of the thrombosed segment of the vein, decreased density mass without intraluminal enhancement of the involved vein, nonvisualization of the portal venous branch in the involved lobe, and the so-called cavernous transformation of the portal vein. The surgically resected gastric specimen showed Borrmann type 3 advanced papillary adenocarcinoma. The portal tumor thrombus is presumed to have arisen from vascular invasion in the primary foci of gastric carcinoma, and then to have permeated the portal vein without invasion of liver parenchyma.     

Increased metalloproteinase activity, oxidant production, and emphysema in surfactant protein D gene-inactivated mice

Targeted ablation of the surfactant protein D (SP-D) gene caused chronic inflammation, emphysema, and fibrosis in the lungs of SP-D (-/-) mice. Although lung morphology was unperturbed during the first 2 weeks of life, airspace enlargement was observed by 3 weeks and progressed with advancing age. Inflammation consisted of hypertrophic alveolar macrophages and peribronchiolar-perivascular monocytic infiltrates. These abnormalities were associated with increased activity of the matrix metalloproteinases, MMP2 and MMP9, and immunostaining for MMP9 and MMP12 in alveolar macrophages. Hydrogen peroxide production by isolated alveolar macrophages also was increased significantly (10-fold). SP-D plays a critical role in the suppression of alveolar macrophage activation, which may contribute to the pathogenesis of chronic inflammation and emphysema.     

Pretherapeutic nutritional/inflammatory factors as predictors for survival of both early and advanced staged head and neck cancer patients

ObjectivesMalnutrition and inflammation are common in patients with head and neck cancer and are closely associated with prognosis. Although several parameters for evaluating nutritional/inflammatory status have been assessed in relation to the prognosis of patients with head and neck cancer, previous studies primarily included patients with advanced-stage disease. To date, there is no consensus regarding the most reliable parameter for predicting the prognosis of early and advanced-stage head and neck cancer. This study sought to evaluate nutritional/inflammatory prognostic factors before treatment in patients with early and advanced-stage head and neck cancer.MethodsWe retrospectively reviewed medical records of patients treated between 2008 and 2015 at our institution in order to evaluate the effects of nutritional/inflammatory parameters, including C-reactive protein/albumin ratio, modified Glasgow prognostic score, neutrophil/lymphocyte ratio, platelet/lymphocyte ratio, and Geriatric Nutritional Risk Index, on overall survival. Effects of potential risk factors on overall survival were analyzed by computing Kaplan-Meier estimates; curves were compared using the log-rank test.ResultsA total of 164 patients were enrolled. C-reactive protein/albumin ratio, modified Glasgow prognostic score, platelet/lymphocyte ratio, and Geriatric Nutritional Risk Index were found to be statistically significantly correlated with overall survival. Only the Geriatric Nutritional Risk Index remained statistically significant in the multivariate analysis. The three-year survival rates according to the four-group Geriatric Nutritional Risk Index scores for normal, low, moderate, and high risk were 95.5%, 84.3%, 53.8%, and 23.4%, respectively.ConclusionThe Geriatric Nutritional Risk Index is therefore a useful prognostic factor for patients with early and advanced-stage head and neck cancer.     

Endoscopy-assisted transoral resection of a parapharyngeal space schwannoma without mandibular dissection

Of the schwannomas that arise from the parapharyngeal space, those in the high cervical region are particularly invasive, requiring mandibular dissection. Because these tumors are benign, however, excessive surgical invasion and postoperative neurological complications should be avoided. Postoperative dropout symptoms may be avoided by intracapsular extraction, including nerve integrity monitoring (NIM) and narrow-band imaging (NBI). Video laryngoscopy surgery is reported to be useful for transoral resection of pharyngeal and laryngeal tumors. This report describes the transoral removal of a giant schwannoma located in the high cervical region from a 74-years-old man using a surgical support device without mandibular dissection.The tumor was located on the right lateral pharyngeal wall and extended from the upper oropharynx to the hypopharynx while compressing the epiglottis to the skull base. No separation was observed between the internal jugular vein and the internal carotid artery. The tumor was diagnosed as a schwannoma with no malignancy on the basis of the histology of a core needle biopsy (CNB), and was completely and safely removed endoscopically using NIM and NBI, with no need for an external incision or mandibular dissection. This case illustrates that even a huge sympathetic schwannoma located in the parapharyngeal space at a high cervical position can be excised transorally using video-laryngoscopic surgery (TOVS) without mandibular dissection.     

Prediction of clinical effects of infliximab administered for inflammatory bowel disease based on pharmacokinetic and pharmacodynamic modeling

Infliximab (IFX) is used as a therapeutic agent for ulcerative colitis (UC) and Crohn's disease (CD). Although the dosage regimen has been established through clinical trial experience, it has yet to be assessed with a pharmacokinetic and pharmacodynamic model. The present study analysed sequential changes of clinical response in patients with ulcerative colitis and Crohn's disease following repeated administrations of infliximab using the pharmacokinetic/pharmacodynamic model. In addition, the dosage regimen presently used for patients with ulcerative colitis was evaluated, as well as the potential efficacy gained by increasing the dose and/or reducing the interval of administration for patients with Crohn's disease. Furthermore, the possibility of evaluating the difference between both diseases with regard to the efficacy of infliximab was investigated. Sequential changes in the clinical response values obtained with our model were in good agreement with the observed values following administration of infliximab in patients with ulcerative colitis and Crohn's disease. The results showed the importance of a loading dose for patients with ulcerative colitis, as well as the efficacy of increasing the dose and reducing the interval for patients with Crohn's disease. Also, the efficacy of infliximab for both diseases is suggested to be similar. In conclusion, our results show a possible modeling scenario that can accommodate the clinical response to infliximab administered for ulcerative colitis and Crohn's disease. Furthermore, it provides confirmation for the present dosage regimens given for these diseases.     

Heat of supersaturation-limited amyloid burst directly monitored by isothermal titration calorimetry

Amyloid fibrils form in supersaturated solutions via a nucleation and growth mechanism. Although the structural features of amyloid fibrils have become increasingly clearer, knowledge on the thermodynamics of fibrillation is limited. Furthermore, protein aggregation is not a target of calorimetry, one of the most powerful approaches used to study proteins. Here, with β₂-microglobulin, a protein responsible for dialysis-related amyloidosis, we show direct heat measurements of the formation of amyloid fibrils using isothermal titration calorimetry (ITC). The spontaneous fibrillation after a lag phase was accompanied by exothermic heat. The thermodynamic parameters of fibrillation obtained under various protein concentrations and temperatures were consistent with the main-chain dominated structural model of fibrils, in which overall packing was less than that of the native structures. We also characterized the thermodynamics of amorphous aggregation, enabling the comparison of protein folding, amyloid fibrillation, and amorphous aggregation. These results indicate that ITC will become a promising approach for clarifying comprehensively the thermodynamics of protein folding and misfolding.Aggregation has often been an obstacle to studying the structure, function, and physical properties of proteins. However, a large number of aggregates associated with serious diseases, including Alzheimer’s, Parkinson, and prion diseases (1, 2) promoted the challenge of studying protein misfolding and aggregation. Researchers succeeded in distinguishing amyloid fibrils and oligomers from other amorphous aggregates and characterized the ordered structures present in amyloid fibrils or oligomers, which led to the development of the field of amyloid structural biology (3–8). These advances have been attributed to various methodologies that are also useful for studying the structural properties of globular proteins. Even X-ray crystallography has become a powerful approach for studying amyloid microcrystals (5) or oligomers (9). The atomic details of amyloid fibrils are becoming increasingly clearer, and a cross-β structure was shown to be the main structural component of fibrils (5, 6, 8). Although tightly packed core regions of amyloid fibrils have been reported, the overall structures were shown to be dominated by common cross-β structures, which supported the argument for the main-chain dominated architecture in contrast to the side-chain dominated architecture of globular native states (10–12).These structural studies have been complemented by a series of efforts to clarify the mechanism for the formation of amyloid fibrils (i.e., amyloid fibrillation). The presence of a long lag time in spontaneous fibrillation and rapid fibrillation by the addition of preformed fibrils represent a similarity with the supersaturation-limited crystallization of substances (13–18). We have revisited “supersaturation” and argued its critical role for amyloid fibrillation (17–19). The role of supersaturation in neurodegenerative diseases at the proteome level has been reported recently (20).However, calorimetry, one of the most powerful methods used to study the thermodynamic properties of globular proteins (21–24), has not played a significant role in understanding protein aggregation. The aggregation of proteins following heat denaturation as monitored by differential scanning calorimetry is an infamous example demonstrating how aggregation can prevent exact analyses (25, 26). To date, few studies have investigated protein aggregation including amyloid fibrils with calorimetry (27–32). Our previous study on the exothermic heat effects accompanying fibril growth was achieved by monitoring the seed-dependent elongation of fibrils formed by β₂-microglobulin (β2m), a protein responsible for dialysis-related amyloidosis, using isothermal titration calorimetry (ITC) (28).In the present study using β2m, we succeeded in characterizing the total heat of spontaneous fibrillation and amorphous aggregation. An analysis of the heat burst associated with fibrillation or amorphous aggregation under various temperatures clarified their thermodynamic properties. The results obtained enabled the calorimetric characterization of amyloid fibrils and amorphous aggregates relative to that of the native globular structures, which opens a new field for the calorimetric study of protein aggregates.