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1.  Pleuroparenchymal Fibroelastosis: Its Clinical Characteristics 
Pleuroparenchymal fibroelastosis (PPFE) is a rare pulmonary fibrosis that is clinically characterized by upper-lobe predominant fibrosis. PPFE is a slowly progressive disorder and its first symptom is dyspnea or dry cough. Chest pain because of pneumothorax may be the first symptom in some patients. Patients with PPFE are slender with a flat rib cage or abnormally narrowed anterior–posterior thoracic dimension. Decreases in forced vital capacity, total lung capacity, and diffusing capacity are respiratory-function characteristics of PPFE, similar to those seen in idiopathic pulmonary fibrosis (IPF). The most remarkable difference in clinical features between PPFE and IPF is imaging findings, with upper-lobe-predominant lesions in PPFE and lower-lobe-predominant lesions in IPF.
doi:10.2174/1573398X0904140129125307
PMCID: PMC3933942  PMID: 24578677
Pleuroparenchymal fibroelastosis (PPFE); pulmonary upper lobe fibrosis; pulmonary fibrosis (IPF).
2.  HIV-1 Resistance Mechanism to an Electrostatically Constrained Peptide Fusion Inhibitor That Is Active against T-20-Resistant Strains 
T-20EK is a novel fusion inhibitor designed to have enhanced α-helicity over T-20 (enfuvirtide) through engineered electrostatic interactions between glutamic acid (E) and lysine (K) substitutions. T-20EK efficiently suppresses wild-type and T-20-resistant variants. Here, we selected T-20EK-resistant variants. A combination of L33S and N43K substitutions in gp41 were required for high resistance to T-20EK. While these substitutions also caused resistance to T-20, they did not cause cross-resistance to other known fusion inhibitors.
doi:10.1128/AAC.00237-13
PMCID: PMC3719727  PMID: 23689710
3.  Low-molecular-weight lipoprotein (a) and low relative lymphocyte concentration are significant and independent risk factors for coronary heart disease in patients with type 2 diabetes mellitus: Lp(a) phenotype, lymphocyte, and coronary heart disease 
Background
The aim of the present prospective study was to examine whether lipoprotein (a) [Lp(a)] phenotypes and/or low relative lymphocyte concentration (LRLC) are independently associated with coronary heart disease (CHD) in patients with type 2 diabetes mellitus (T2DM).
Methods
Serum Lp(a) concentration, Lp(a) phenotypes, and RLC were analyzed in 214 subjects. Lp(a) phenotypes were classified into 7 subtypes according to sodium dodecyl sulfate-agarose gel electrophoresis by Western blotting. Subjects were assigned to the low-molecular-weight (LMW (number of KIV repeats: 11–22) ) and high-molecular-weight (HMW( number of KIV repeats: >22 )) Lp(a) groups according to Lp(a) phenotype and to the LRLC (RLC: <20.3%) and normal RLC (NRLC; RLC: ≥20.3%) groups according to RLC. A CHD event was defined as the occurrence of angina pectoris or myocardial infarction during the follow-up period.
Results
During the follow-up period, 30 cases of CHD events were verified. Neutrophil count showed no correlation with CHD, while relative neutrophil concentration and RLC showed positive and negative correlations, respectively, with CHD. The Cox proportional hazard model analysis revealed the following hazard ratios adjusted for LMW Lp(a), LRLC, and LMW Lp(a) + LRLC: (4.31; 95% confidence interval [CI], 1.99-9.32; P < 0.01, 3.621; 95% CI, 1.50-8.75; P < 0.05, and 7.15; 95% CI, 2.17-23.56; P < 0.01, respectively).
Conclusions
Our results suggest that both LMW Lp(a) and LRLC are significant and independent risk factors for CHD and that the combination thereof more strongly predicts CHD in patients with T2DM.
doi:10.1186/1476-511X-12-31
PMCID: PMC3606419  PMID: 23496967
Lipoprotein (a) phenotype; Relative lymphocyte concentration; Coronary heart disease
4.  Relationship between postprandial glucose level and carotid artery stiffness in patients without diabetes or cardiovascular disease 
Background
The aim of this study was to evaluate the relationship between postprandial glucose level and atherosclerosis in patients without diabetes and cardiovascular disease by determining carotid ultrasonographic variables and serum levels of 1,5-anhydroglucitol (1,5-AG).
Methods
The subjects were 72 patients without diabetes and cardiovascular disease being treated for hypertension or dyslipidemia. The clinical characteristics of all subjects, including the serum level of 1,5-AG, which appears to be well suited for monitoring postprandial hyperglycemia, were evaluated after an overnight fast. The average intima-media thickness (IMT) and the average pulsatility index (PI) of the right and left common carotid arteries were determined with high-resolution ultrasonography and used as ultrasonographic variables. The subjects were divided into a Lower 1,5-AG group (n = 36) and a Higher 1,5-AG group (n = 36). We evaluated the relationship between clinical characteristics and ultrasonographic variables of the carotid artery in both groups.
Results
The average PI in the Lower 1,5-AG group was significantly higher than that in the Higher 1,5-AG group, but the average IMT did not differ between the groups. Linear regression analysis, with the ultrasonographic variables as the dependent variables, with 1,5-AG as the independent variable, and adjusted for other clinical characteristics, showed significant correlation between 1,5-AG and the PI but not between 1,5-AG and IMT.
Conclusion
Our results suggest that postprandial hyperglycemia increases carotid artery stiffness, but not morphological change, in patients without diabetes or cardiovascular disease.
doi:10.1186/1471-2261-13-11
PMCID: PMC3598373  PMID: 23442745
1,5-anhydroglucitol; Pulsatility index; Postprandial glucose; Nondiabetic patients
5.  The effects of postprandial glucose and insulin levels on postprandial endothelial function in subjects with normal glucose tolerance 
Background
Previous studies have demonstrated that postprandial hyperglycemia attenuates brachial artery flow-mediated dilation (FMD) in prediabetic patients, in diabetic patients, and even in normal subjects. We have previously reported that postprandial hyperinsulinemia also attenuates FMD. In the present study we evaluated the relationship between different degrees of postprandial attenuation of FMD induced by postprandial hyperglycemia and hyperinsulinemia and differences in ingested carbohydrate content in non-diabetic individuals.
Methods
Thirty-seven healthy subjects with no family history of diabetes were divided into 3 groups: a 75-g oral glucose loading group (OG group) (n = 14), a test meal group (TM group) (n = 12; 400 kcal, carbohydrate content 40.7 g), and a control group (n = 11). The FMD was measured at preload (FMD0) and at 60 minutes (FMD60) and 120 (FMD120) minutes after loading. Plasma glucose (PG) and immunoreactive insulin (IRI) levels were determined at preload (PG0, IRI0) and at 30 (PG30, IRI30), 60 (PG60, IRI60), and 120 (PG120, IRI120) minutes after loading.
Result
Percentage decreases from FMD0 to FMD60 were significantly greater in the TM group (−21.19% ± 17.90%; P < 0.001) and the OG group (−17.59% ± 26.64%) than in the control group (6.46% ± 9.17%; P < 0.01), whereas no significant difference was observed between the TM and OG groups. In contrast, the percentage decrease from FMD0 to FMD120 was significantly greater in the OG group (−18.91% ± 16.58%) than in the control group (6.78% ± 11.43%; P < 0.001) or the TM group (5.22% ± 37.22%; P < 0.05), but no significant difference was observed between the control and TM groups. The FMD60 was significantly correlated with HOMA-IR (r = −0.389; P < 0.05). In contrast, FMD120 was significantly correlated with IRI60 (r = −0.462; P < 0.05) and the AUC of IRI (r = −0.468; P < 0.05). Furthermore, the percentage change from FMD0 to FMD120 was significantly correlated with the CV of PG (r = 0.404; P < 0.05), IRI60 (r = 0.401; p < 0.05) and the AUC of IRI (r = 0.427; P < 0.05). No significant correlation was observed between any other FMDs and glucose metabolic variables.
Conclusion
Differences in the attenuation of postprandial FMD induced by different postprandial insulin levels may occur a long time postprandially but not shortly after a meal.
doi:10.1186/1475-2840-11-98
PMCID: PMC3471039  PMID: 22891922
Flow-mediated dilation; Carbohydrate content; Postprandial; Glucose metabolism; Non-diabetic individuals
6.  Prognostic value of immunohistochemical surfactant protein A expression in regenerative/hyperplastic alveolar epithelial cells in idiopathic interstitial pneumonias 
Diagnostic Pathology  2011;6:25.
Background
It is difficult to predict survival in patients with idiopathic pulmonary fibrosis. Recently, several proteins, such as surfactant protein (SP) and KL-6, have been reported to be useful biologic markers for prediction of prognosis for interstitial pneumonias. It is not clear whether there is any relationship between expression of these proteins in regenerative/hyperplastic alveolar epithelial cells and prognosis of idiopathic interstitial pneumonias (IIPs).
Objectives
This study aimed to elucidate the clinical significance of the expression of such lung secretory proteins as SP-A and KL-6 in lung tissues of patients with IIPs.
Methods
We retrospectively investigated the immunohistochemical expression of SP-A, KL-6, cytokeratin (CK), and epithelial membrane antigen (EMA) in alveolar epithelial cells in lung tissues obtained from surgical lung biopsy in 43 patients with IIPs, and analyzed the correlation between expression of these markers and the prognosis of each IIP patient. CK and EMA were used as general markers for epithelial cells.
Results
In patients with usual interstitial pneumonia (UIP), the ratio of SP-A positive epithelial cells to all alveolar epithelial cells (SP-A positive ratio) in the collapsed and mural fibrosis areas varied, ranging from cases where almost all alveolar epithelial cells expressed SP-A to cases where only a few did. On the other hand, in many patients with nonspecific interstitial pneumonia (NSIP), many of the alveolar epithelial cells in the diseased areas expressed SP-A. The SP-A positive ratio was significantly lower in patients who died from progression of UIP than in patients with UIP who remained stable or deteriorated but did not die. In NSIP patients, a similar tendency was noted between the SP-A positive ratio and prognosis.
Conclusions
The results suggest that the paucity of immunohistochemical SP-A expression in alveolar epithelial cells in diseased areas (i.e. regenerative/hyperplastic alveolar epithelial cells) may predict a worse prognosis for patients with IIPs, especially patients with UIP. A prospective study is needed to confirm these results.
doi:10.1186/1746-1596-6-25
PMCID: PMC3072304  PMID: 21435274
7.  SC29EK, a Peptide Fusion Inhibitor with Enhanced α-Helicity, Inhibits Replication of Human Immunodeficiency Virus Type 1 Mutants Resistant to Enfuvirtide ▿  
Peptides derived from the α-helical domains of human immunodeficiency virus (HIV) type 1 (HIV-1) gp41 inhibit HIV-1 fusion to the cell membrane. Enfuvirtide (T-20) is a peptide-based drug that targets the step of HIV fusion, and as such, it effectively suppresses the replication of HIV-1 strains that are either wild type or resistant to multiple reverse transcriptase and/or protease inhibitors. However, HIV-1 variants with T-20 resistance have emerged; therefore, the development of new and potent inhibitors is urgently needed. We have developed a novel HIV fusion inhibitor, SC34EK, which is a gp41-derived 34-amino-acid peptide with glutamate (E) and lysine (K) substitutions on its solvent-accessible site that stabilize its α-helicity. Importantly, SC34EK effectively inhibits the replication of T-20-resistant HIV-1 strains as well as wild-type HIV-1. In this report, we introduce SC29EK, a 29-amino-acid peptide that is a shorter variant of SC34EK. SC29EK blocked the replication of T-20-resistant HIV-1 strains and maintained antiviral activity even in the presence of high serum concentrations (up to 50%). Circular dichroism analysis revealed that the α-helicity of SC29EK was well maintained, while that of the parental peptide, C29, which showed moderate and reduced inhibition of wild-type and T-20-resistant HIV-1 strains, was lower. Our results show that the α-helicity in a peptide-based fusion inhibitor is a key factor for activity and enables the design of short peptide inhibitors with improved pharmacological properties.
doi:10.1128/AAC.01211-08
PMCID: PMC2650564  PMID: 19114674
8.  Drug interaction prediction using ontology-driven hypothetical assertion framework for pathway generation followed by numerical simulation 
BMC Bioinformatics  2008;9(Suppl 6):S11.
Background
In accordance with the increasing amount of information concerning individual differences in drug response and molecular interaction, the role of in silico prediction of drug interaction on the pathway level is becoming more and more important. However, in view of the interferences for the identification of new drug interactions, most conventional information models of a biological pathway would have limitations. As a reflection of real world biological events triggered by a stimulus, it is important to facilitate the incorporation of known molecular events for inferring (unknown) possible pathways and hypothetic drug interactions. Here, we propose a new Ontology-Driven Hypothetic Assertion (OHA) framework including pathway generation, drug interaction detection, simulation model generation, numerical simulation, and hypothetic assertion. Potential drug interactions are detected from drug metabolic pathways dynamically generated by molecular events triggered after the administration of certain drugs. Numerical simulation enables to estimate the degree of side effects caused by the predicted drug interactions. New hypothetic assertions of the potential drug interactions and simulation are deduced from the Drug Interaction Ontology (DIO) written in Web Ontology Language (OWL).
Results
The concept of the Ontology-Driven Hypothetic Assertion (OHA) framework was demonstrated with known interactions between irinotecan (CPT-11) and ketoconazole. Four drug interactions that involved cytochrome p450 (CYP3A4) and albumin as potential drug interaction proteins were automatically detected from Drug Interaction Ontology (DIO). The effect of the two interactions involving CYP3A4 were quantitatively evaluated with numerical simulation. The co-administration of ketoconazole may increase AUC and Cmax of SN-38(active metabolite of irinotecan) to 108% and 105%, respectively. We also estimates the potential effects of genetic variations: the AUC and Cmax of SN-38 may increase to 208% and 165% respectively with the genetic variation UGT1A1*28/*28 which reduces the expression of UGT1A1 down to 30%.
Conclusion
These results demonstrate that the Ontology-Driven Hypothetic Assertion framework is a promising approach for in silico prediction of drug interactions. The following future researches for the in silico prediction of individual differences in the response to the drug and drug interactions after the administration of multiple drugs: expansion of the Drug Interaction Ontology for other drugs, and incorporation of virtual population model for genetic variation analysis, as well as refinement of the pathway generation rules, the drug interaction detection rules, and the numerical simulation models.
doi:10.1186/1471-2105-9-S6-S11
PMCID: PMC2423434  PMID: 18541046
9.  Urinary N-acetyl-β-d-Glucosaminidase Levels are Positively Correlated With 2-Hr Plasma Glucose Levels During Oral Glucose Tolerance Testing in Prediabetes 
Background
Urinary N-acetyl-β-D-glucosaminidase (NAG) excretion is increased in patients with impaired glucose tolerance (IGT). This study investigated when during the oral glucose tolerance test (OGTT) the plasma glucose, urine glucose, and insulin levels correlate most strongly with urinary N-acetyl-β-d-glucosaminidase (NAG) levels in prediabetic subjects.
Methods
The OGTT was administered to 80 subjects who had not yet received a diagnosis of diabetes mellitus (DM) and in whom HbA1c levels were ≤6.8% and fasting plasma glucose levels were <7.0 mmol/l. Forty-two subjects had normal glucose tolerance (NGT), 31 had impaired glucose tolerance (IGT), and 7 had DM according to World Health Organization criteria. Serum levels of cystatin C, the estimated glomerular filtration rate, the urinary albumin-to-creatinine (Cr) ratio, urinary and serum β2-microglobulin, and urinary NAG were measured as markers of renal function.
Results
NAG levels were significantly higher in subjects with DM and in subjects with IGT than in subjects with NGT. No significant associations were observed between glycemic status and other markers of renal function. Multiple linear regression analysis showed that the NAG level was positively correlated with plasma glucose levels at 120 min of the OGTT and was associated with the glycemic status of prediabetic patients.
Conclusion
These results suggest that postprandial hyperglycemia is an independent factor that causes renal tubular damage in prediabetes patients.
doi:10.1002/jcla.21549
PMCID: PMC3558795  PMID: 23143631
cystatin C; N-acetyl-β-d-glucosaminidase; tubular dysfunction; impaired glucose tolerance; diabetic nephropathy

Results 1-9 (9)