Assessment of biological, psychological and adherence factors in the prediction of step-down treatment for patients with well-controlled asthma.

BACKGROUND AND OBJECTIVE: Inhaled corticosteroids (ICS) and inhaled corticosteroids combined with long-acting beta2-agonist (ICS/LABA) are standard treatments for asthma. However, factors that might help reduce medication in well-controlled asthma are unknown. We classified problems of asthma patients into biological, psychological and adherence factors, and investigated factors associated with the indication and failure of a medication step-down treatment. METHODS: Two hundred twenty two well-controlled asthma patients receiving ICS or ICS/LABA were assessed for physical and psychiatric problems and followed up for one year from adjustment of their treatment step. Factor B was defined as a presence of chronic upper airway complications. Factor P was defined as presence of psychiatric complications such as sleep disorder, depression, anxiety and somatoform disorders. Factor A was defined as poor adherence to ICS or ICS/LABA inhaler of 75% or less. Success in step-down treatment was defined as maintenance of well-controlled status for over one year after step-down. RESULTS: Factor B was the most important single negative predictive factor for indication for step-down treatment (Odds ratio; 0.19). Factor A increased the risk of failure to maintain step-down treatment most significantly by 23-fold, and factor B increased it by 11-fold. The combination of factors B and A increased failure by 24-fold, factors P and A by 21-fold, all three factors by 36-fold. Factor P only interacted with the other factors to reduce chances of stepping down, but did not constitute a problem factor when present alone. CONCLUSION AND CLINICAL RELEVANCE: The evaluation of biological, psychological and adherence problems may lead to a more proactive and targeted approach to step-down treatment for patients with well-controlled asthma.

Fungal meningitis caused by Lomentospora prolificans after allogeneic hematopoietic stem cell transplantation.

Central nervous system lomentosporiosis is a rare pathological condition in immunocompromised patients. We describe a fatal case of meningitis caused by Lomentospora prolificans (which was previously named Scedosporium prolificans), after an allogeneic hematopoietic stem cell transplantation (allo-HSCT). To our knowledge, no cases of Lomentospora meningitis following allo-HSCT have been reported previously. Particularly in neutropenic patients, it is important to consider L. prolificans when a fungal infection is suspected and antifungal agents are ineffective.

Maximum flexion and lateral rollback revealed better patient satisfaction after total knee arthroplasty.

INTRODUCTION: Patient satisfaction is an important outcome of total knee arthroplasty (TKA). However, we cannot predict how and why patients are satisfied or dissatisfied with TKA. The hypothesis of this study was that patient-reported outcomes (PROs) correlate with in vivo kinematics after TKA. MATERIALS AND METHODS: One hundred knees were analyzed after TKA. The in vivo kinematics of deep knee bending motion were estimated from single-plane fluoroscopy using a two-to-three-dimensional registration technique. Active knee flexion, femoral rotation and rollback were evaluated. The PROs were obtained after surgery using the 2011 Knee Society Scoring System (KSS), and their relationship with in vivo kinematics was determined. RESULTS: The average minimum and maximum flexion were -2.4 ± 7.3° and 113.2 ± 13.6°, respectively. The average femoral rotation was 7.4 ± 3.4°, and the average medial and lateral rollback were 2.4 ± 4.8 mm and 7.2 ± 5.6 mm, respectively. The multiple regression analysis revealed that the maximum flexion angle significantly contributed to symptoms and satisfaction. In addition, lateral rollback was also a significant factor affecting patient satisfaction. Lateral rollback and lateral Anterior-Posterior (AP) position at maximum flexion were correlated with the maximum flexion angle, whereas femoral rotation did not correlate with flexion angles. CONCLUSIONS: Maximum flexion and lateral rollback are important for better patient satisfaction after TKA. To obtain the maximum flexion angle, it was necessary to perform the normal kinematic pattern with a large amount of lateral rollback.

Retinoic acids up-regulate functional eosinophil-driving receptor CCR3.

Eotaxins and their receptor CCR3 have a definitive role for tissue accumulation of eosinophils both under homeostatic and pathologic conditions. However, physiological stimuli that can up-regulate CCR3 in blood-derived human eosinophils have not been recognized. As a prior gene microarray study revealed up-regulation of CCR3 in eosinophils stimulated with retinoic acids (RAs), the expression of functional CCR3 was examined. We found that 9-cis RA and all-trans RA (ATRA) significantly induced surface CCR3 expression regardless of the presence of IL-3 or IL-5. Pharmacological manipulations with receptor-specific agonists and antagonists indicated that retinoic acid receptor-α activation is critical for CCR3 up-regulation. RA-induced CCR3 was associated with its functional capacity, in terms of the calcium mobilization and chemotactic response to eotaxin-1 (CCL11). Our study suggests an important role of vitamin A derivatives in the tissue accumulation of eosinophils.

Erythromycin-resistant mutant of Escherichia coli with altered ribosomal protein component.

Erythromycin combines with 50S ribosomal subunit of an erythromycin-sensitive Escherichia coli (strain Q13), while ribosomes from an erythromycin-resistant mutant from this strain have little affinity for the antibiotic. A protein component of the 50S subunit of the mutant strain is distinct from that of the parent Q13 strain.

[Mediastinal lymph node carcinoma of unknown primary site; report of a case].

A 44-year-old woman was admitted to our hospital because of mediastinal mass. Serum levels of carcinoembryonic antigen (CEA) were found to be elevated. No preoperative examination could detect the primary lesion. The tumor was resected through right thoracotomy. Histological examination revealed poorly differentiated adenocarcinoma. She was diagonosed as metastatic mediastinal lymph node carcinoma of unknown primary site. She received radiotherapy and chemotherapy and is desease free 29 months after operation. Good results may be obtained by multimodality therapies for cancer in mediastinal lymph node of unknown primary site.

[Giant left atrial myxoma with ossification on having a fever; report of a case].

A 37-year-old female with a fever had a medical examination, and was pointed out cardiac murmur. She was referred to our hospital for a further examination. Blood cultures were positive for Streptococcus milleri group. Thoracic echocardiogram demonstrated a giant left atrial tumor, arising from the portion of the interatrial septum, and mitral insufficiency. We removed the tumor completely and performed mitral annuloplasty. The tumor was diagnosed as myxoma with ossification by histopathological examination. She discharged from our hospital 25 days after the operation without complication and does not recur for 3 years. We consider our case as extremely rare, because it revealed giant left atrial myxoma with ossification and mitral insufficiency at the same time.

[Repeated catamenial pneumothorax with pleural and diaphragmatic endometriosis; report of a case].

A 31-year-old female with 2 episodes of right pneumothorax related to onset of menstruation was reported. Thoracoscopy revealed the presence of some cystic lesions in the diaphragm. Partial resection of the diaphragm including the lesions was performed. Histologial findings of the resected diaphragm showed stromal endometriosis. One month after operation, she had a recurrent right pneumothorax related to onset of menstruation. A pinhole perforation of the lower lobe was noted at 2nd surgery. Microscopic examination of the resected lung disclosed endometrial stroma in the macroscopically normal lung tissue. Since air leakage from chest tube continued after surgery, the hormonal therapy with a gonadotropin-releasing hormone analogue was started, and she was discharged from the hospital 3 weeks after hormonal therapy. Report of the demonstration of endmetriosis in the visceral pleura and diaphragm is very rare and the present case is very suggestive is considering the mechanism of the development of this disease.

The second offshore production of methane hydrate in the Nankai Trough and gas production behavior from a heterogeneous methane hydrate reservoir.

Following the first attempt at producing gas from a naturally occurring methane hydrate (MH) deposit in the Daini-Atsumi Knoll in the eastern Nankai Trough area off Honshu Island, Japan in 2013, a second attempt was made in April to June of 2017 at a nearby location using two producer wells sequentially and applying the depressurization method. The operation in the first borehole (AT1-P3) continued for 12 days with a stable drawdown of around 7.5 MPa and 41 000 m3 of methane gas being produced despite intermittent sand-production events. The operation of the other borehole (AT1-P2) followed, with a total of 24 days of flow and 222 500 m3 of methane gas being produced without sand problems. However, the degree of drawdown was limited to 5 MPa because of a higher water production rate than expected in the second hole. The pressure and temperature sensors deployed in the two producers, along with the two monitoring holes drilled nearby, gathered reservoir response data and information about the long-term MH dissociation processes in the vicinity of the production holes in the temporal and spatial domains. Although the ratio of energy return to the input was considerably larger than that for the depressurization operation, some observations (e.g., the high contrast in the production rates between the two holes and the almost constant or slightly reduced gas production rates) were not predicted by the numerical models. This failure in prediction raises questions about the veracity of the reservoir characteristics modeled in the numerical simulations. This paper presents the operation summaries and data obtained with thought-experiment based-anticipated production behaviors and preliminary analysis of the obtained data as the comparison with expected behaviors. Detailed observations of gas and water production, as well as the pressure and temperature data recorded during the gas flow tests, indicate that the heterogeneous MH distribution within the reservoir was mainly responsible for the discrepancies observed between the anticipated and actual behaviors. Furthermore, the motion of the water that does not originate from MH dissociation introduces complexity, such as the occurrence of concentrated water-producing intervals and unexpected gas production responses to decreases in pressure, into the production behavior. The influence of heterogeneity should be clearly understood for the accurate prediction of gas production behavior based on MH reservoirs.

[Congenital chylothorax treated with video-assisted thoracic surgery].

A 35-day-old female was referred to our department because of congenital chylothorax. Medical treatment with dietary restriction was undertaken for 5 weeks without resolution of the effusion. A video-assisted thoracic surgery was performed. The mediastinal pleura was covered with fibrin glue. The postoperative course was satisfactory. She was discharged with resolution of the effusion. Video-assisted thoracic surgery offers an effective means of treating chylothorax.

Effectiveness and safety of a new regimen of polyethylene glycol plus ascorbic acid for same-day bowel cleansing in constipated patients.

BACKGROUND AND STUDY AIMS: In an exploratory study we compared a new regimen of low-volume polyethylene glycol plus ascorbic acid (PEG-Asc) with the standard regimen for same-day bowel cleansing in constipated patients. PATIENTS AND METHODS: Between January and June 2015 we studied consecutive patients with constipation (Rome III constipation criteria) scheduled for colonoscopy. The initial group received the standard regimen of PEG-Asc. The subsequent group received the new regimen. The new regimen involved ingestion of 10 mL of sodium picosulfate and 50g of magnesium citrate dissolved in 0.2 L of water followed by 0.2 L of PEG-Asc +0.2 L of water given 6 or 7 times over 3 hours. Bowel cleansing was prospectively evaluated using the Boston bowel preparation scale (BBPS). Bowel cleansing, adenoma detection rates and adverse events were reviewed using electronic medical records and endoscopic filing system. RESULTS: Sixty-two patients used the standard regimen and sixty used the new regimen. The basic characteristics of the two groups were similar. The mean volume of PEG-Asc and total liquid intake was less with the new regimen compared to the standard regimen (1.3 L vs. 2.0 L, P<0.001; 2.6 L vs. 3.0 L, P<0.001). The proportion of patients with a BBPS score ≥ 6 was significantly greater with the new than the standard regimen (93% vs. 76%, P=0.008). Nausea and/or vomiting was also significantly less frequent than with the standard regimen (5% vs. 16%, P=0.046). CONCLUSIONS: The new regimen of PEG-Asc gave improved same-day bowel cleansing for colonoscopy in constipated patients.

Characterization of recombinant human and rat pancreatic phospholipases A2 secreted from Saccharomyces cerevisiae: difference in proteolytic processing.

An expression plasmid for human pancreatic phospholipase A2 in Saccharomyces cerevisiae was constructed by insertion of cDNA encoding its preprophospholipase A2 into a yeast expression vector pAM82. The resulting product secreted in the yeast culture medium was mainly prophospholipase A2, which was the same as the natural proenzyme in all aspects examined, including the higher order structure. However, when the rat preprophospholipase A2 cDNA was manipulated in the same manner, the active phospholipase A2 of the intact mature form was secreted with the proenzyme being hardly detected in the medium. This unexpected favorable result would occur due to cleavage of rat phospholipase A2 pro-peptide by a trypsin-like proteinase in S. cerevisiae. Based on this finding, we constructed a plasmid carrying the sequence coding for the prepro-peptide of rat pancreatic phospholipase A2 behind the PHO5 promoter in the pAM82 vector, which leads to the secretion of heterologous proteins as their mature form. The use of this plasmid led to secretion of biologically active human pancreatic secretory trypsin inhibitor and a glutamic acid-specific endopeptidase from Staphylococcus aureus ATCC 12600, which are eukaryote and prokaryote proteins, respectively, in the culture medium of S. cerevisiae.

Presence of pancreatic-type phospholipase A2 mRNA in rat gastric mucosa and lung.

The content of mRNA for a pancreatic-type phospholipase A2 present in rat gastric mucosa was much greater than that in pancreas. In lung the mRNA for this pancreatic-type phospholipase A2 was also detected, but less than in pancreas. Nucleotide sequence analysis showed that these pancreatic-type phospholipase A2 cDNAs derived from rat gastric mucosa and lung were completely identical to that from rat pancreas (Ohara et al. (1986) J. Biochem. 99, 733-739). This demonstrates that the pancreatic-type phospholipase A2 present in gastric mucosa and lung does not originate from pancreas.

Purification, characterization and molecular cloning of an acidic amino acid-specific proteinase from Streptomyces fradiae ATCC 14544.

We have isolated a novel acidic amino-acid-specific proteinase from Streptomyces fradiae ATCC 14544, using benzyloxycarbonyl-L-Phe-L-Leu-L-Glu-p-nitroanilide (Z-Phe-Leu-Glu-pNA) as a substrate. A proteinase, which we propose to call SFase, was purified from the culture filtrate by salting out, repeated S-Sepharose chromatography, and affinity chromatography (CH-Sepharose-Phe-Leu-D-Glu-OMe). The purified enzyme showed a single band having an apparent molecular weight of 19,000 on sodium dodecyl sulfate polyacrylamide gel electrophoresis. When synthetic peptides were used as substrates, SFase showed high specificity for Z-Phe-Leu-Glu-pNA. Comparison with nitroanilides of glutamic acid and aspartic acid as substrates revealed that the reactivity was about 10-fold higher for a glutamyl bond than an aspartyl bond. SFase selectively hydrolyzed the -Glu-Ala-bond of two glutamyl bonds in the oxidized insulin B-chain within the initial reaction time until the starting material was completely digested. Diisopropylfluorophosphate and benzyloxycarbonyl-Phe-Leu-Glu chloromethylketone completely inhibited SFase, while metalloproteinase inhibitors, such as EDTA and o-phenanthrolin, did not inhibit the enzyme. The findings indicate that SFase can be classified as a serine proteinase, and is highly specific for a glutamyl bond in comparison with an aspartyl bond. To elucidate the complete primary structure and precursor of SFase, its gene was cloned from genomic DNA of the producing strain, and the nucleotide sequence was determined. Consideration of the N- and C-terminal amino-acid sequences of the mature protein of SFase indicates that it consists of 187 amino acids, which follows a prepropeptide of 170 residues. In comparison with the acidic amino-acid-specific proteinase from Streptomyces griseus (Svendsen, I., Jensen, M.R. and Breddam, K. (1991) FEBS Lett. 292, 165-167), SFase had 82% homology in the amino acid sequence. The processing site for maturation of SFase was a unique sequence (-Glu-Val-), so that the propeptide could be released by cleavage of the peptide bond between Glu and Val.

Involvement of agouti-related protein, an endogenous antagonist of hypothalamic melanocortin receptor, in leptin action.

To understand the role of agouti-related protein (AGRP), an endogenous antagonist of hypothalamic melanocortin receptor, in leptin action, we produced a full-length recombinant AGRP and examined its effect on the satiety effect of leptin. We also studied leptin's regulation of hypothalamic AGRP mRNA expression. A single intracerebroventricular (i.c.v.) injection of AGRP significantly increased cumulative food intake and body weight in a dose-dependent manner in rats. The leptin-induced inhibition of food intake and body weight was reversed by co-injection of AGRP in a dose-dependent manner. Hypothalamic AGRP mRNA expression was upregulated in leptin-deficient ob/ob mice and leptin receptor-deficient db/db mice and downregulated in lethal yellow agouti mice (KKAy mice) with hyperleptinemia. A single i.c.v. injection of leptin reversed the increased AGRP mRNA levels in ob/ob mice but not in db/db mice. In control mice and KKAy mice, AGRP mRNA expression was upregulated during fasting, when plasma leptin concentrations were decreased. No significant increase in AGRP mRNA expression was noted during fasting in control mice and KKAy mice treated with leptin. This study provides the first direct evidence that AGRP is a negative regulator of leptin action, and leptin downregulates hypothalamic AGRP production. Because leptin is shown to increase hypothalamic alpha-melanocyte stimulating hormone (alpha-MSH) production, our data suggest that its action via the hypothalamic melanocortin system is determined by the balance between the levels of its agonist and antagonist, alpha-MSH and AGRP.

Primary culture of chicken hepatocytes in serum-free medium (pH 7.8) secreted albumin and transferrin for a long period in free gas exchange with atmosphere.

To study liver functions of chicken, we examined the primary culture of chicken hepatocytes, and found an easy method of long-term culture with free atmosphere exchange. Chicken hepatocytes were obtained by collagenase perfusion and cultured at 37 degrees C as a monolayer without substratum in serum-free L-15 medium (pH 7.8) with free atmosphere exchange. The amounts of albumin and transferrin in medium were assayed by ELISA. The culture of chicken hepatocytes was maintained in the serum-free L15-medium )pH 7.) and 37 degrees C with free atmosphere exchange for 20 days. The amount of albumin secreted in the medium decreased to low levels early in culture; however, this was followed by marked increase from day 9 to day 17 of culture. The amount of transferrin was constant until day 6, then it too increased with further culture. We reported an easy method for the simple monolayer culture of chicken hepatocytes in serum-free L12 medium (pH 7.8) with free atmosphere exchange over an extended period. Expression of liver-specific functions, viz. albumin and transferrin synthesis, was observed after 1 week of culture.

Suppression of episodic growth hormone secretion in streptozotocin-induced diabetic mice: time-course studies on the hypothalamic pituitary axis.

To elucidate the roles of the hypothalamic peptides, GH-releasing hormone (GRH) and somatostatin (SRIH), potentially responsible for altered GH dynamics in diabetes, we studied the time courses of their changes in level associated with altered GH secretion in streptozotocin (STZ)-induced diabetic mice. Diabetic mice were used at 4, 7, and 14 days after STZ injection for analyses of 1) GH secretion in vivo, 2) hypothalamic GRH and SRIH messenger RNA (mRNA) levels, 3) pituitary GH mRNA and protein contents, and 4) pituitary GH response to GRH in vitro. GH secretion was completely suppressed 7 and 14 days after STZ injection. The hypothalamic GRH mRNA level was reduced to 59.8%, 61.2%, and 48.5% of control values at 4, 7, and 14 days, respectively. In contrast, the hypothalamic SRIH mRNA level was not altered at all of these time points. Pituitary GH mRNA and protein contents were significantly reduced to 70.2% and 61.5% of those in controls, respectively, only at 14 days. Pituitary GH responses to GRH at three doses (10, 50, and 250 nM) in vitro were remarkably increased at 4, 7, and 14 days. These findings indicate that the diabetic state rapidly and primarily inhibits hypothalamic GRH gene expression without affecting SRIH. A persistent decrease in hypothalamic GRH tone has been suggested to result in inhibition of GH synthesis in the pituitary. Enhancement of GH responsiveness to GRH may be due to the up-regulation of GRH receptors in the pituitary.

Inhibitory effects of interleukin-1 on growth hormone secretion in conscious male rats.

Although various pathophysiological effects of interleukin (IL) on the CRF-ACTH-adrenal axis and gonadotropin secretion have been studied extensively, the effects of IL on GH secretion still remain to be elucidated. We investigated the possible effects of IL on GH secretion in six groups of conscious rats. In four groups, IL was administered by continuous iv infusion and in the other two, by intracerebroventricular injection. Saline-treated rats served as controls for these groups. Sequential blood sampling was performed every 20 min in all groups, and the plasma GH concentration was determined by RIA. The expression of hypothalamic c-fos protein in a separate group was examined by immunohistochemistry. Continuous infusion of both IL-1 alpha and IL-1 beta (10 ng/min) significantly inhibited GH surges. The plasma IL-1 level was elevated to 2-3 ng/ml. Continuous iv infusion of IL-2 and IL-6 had no effect on GH secretion. The intracerebroventricular injection of both IL-1 alpha and IL-1 beta significantly inhibited GH surges, and the inhibitory effect was much greater for IL-1 beta than for IL-1 alpha. Continuous iv infusion of IL-1 beta markedly stimulated c-fos expression in specific hypothalamic nuclei, particularly in the paraventricular nucleus. These findings suggest that, in the rat, IL-1 inhibits GH secretion through its peripheral and central actions.

Pathophysiological significance of the obese gene product, leptin, in ventromedial hypothalamus (VMH)-lesioned rats: evidence for loss of its satiety effect in VMH-lesioned rats.

To explore the pathophysiological significance of the obese (ob) gene product, leptin, in ventromedial hypothalamus (VMH)-lesioned rats, we examined the synthesis and secretion of leptin and its satiety effect in VMH-lesioned rats compared with those in sham-operated rats. Northern blot analysis revealed that ob gene expression is markedly augmented in the mesenteric and sc white adipose tissue, but remained unchanged in the epididymal white adipose tissue during the development of obesity in VMH-lesioned rats. Plasma leptin levels were relatively constant in sham-operated rats, but were elevated during the development of obesity in VMH-lesioned rats. In sham-operated rats, a single i.v. (1.0 mg/rat) or intracerebroventricular (2.0 micrograms/rat) injection of recombinant human leptin reduced food intake and body weight gain in sham-operated rats. By contrast, no significant effect on food intake or body weight gain was observed in VMH-lesioned rats. The present study provides evidence that VMH-lesioned rats overproduce leptin and increase its release but cannot respond to it and suggests that the loss of its satiety effect contributes to the development of obesity and the obesity-related phenotypes in VMH-lesioned rats.

Cell-dependent replication potentials of HIV-1 gag mutants.

An infectious molecular clone of human immunodeficiency virus type 1 (HIV-1), designated pNLaiKH, which is tropic for both lymphocytic and monocytic cells, was constructed. To study the early function of HIV-1 Gag proteins in two types of cells, the mutations known to give host cell-dependent early defects were introduced into pNLaiKH, and the replication potentials and defective replication sites in the cells of the resultant mutants were monitored. All mutants grew in some lymphocytic cells, but not at all in monocytic cells. A nucleocapsid mutant was found to be defective at an early replication phase in all the cell lines to various extent, as expected. In contrast, a matrix mutant and a capsid mutant displayed a replication defect in a producer-cell-dependent manner. These results demonstrated that complex interactions of cell factors and Gag proteins are involved in an early process of HIV-1 replication.