Health-related quality of life does not predict mortality in idiopathic pulmonary fibrosis.

BACKGROUND: Although health-related quality of life (HRQL) has recently been considered to be an important outcome in clinical trials of idiopathic pulmonary fibrosis (IPF), its relationship with survival is unknown. OBJECTIVE: To determine the prognostic significance of HRQL scores in IPF assessed with the SGRQ. DESIGN: Eighty-seven consecutive patients with IPF, who had undergone evaluations and completed the St. George's Respiratory Questionnaire (SGRQ) at diagnosis were included in this study, as is the general practice. Cox proportional hazards analyses were performed to examine the relationship between HRQL scores and survival. RESULTS: The mean observation period was 44.2 +/- 29.6 mo, in the course of which 54 patients (62.0%) died. Univariate analysis revealed that the activity scores in the SGRQ(HR: 1.016, 95% CI: 1.004-1.029, P = 0.01) were significantly predictive of survival, although the symptoms, impacts, and total scores were not significantly related to mortality from all causes. However, multivariate analysis revealed that only the forced vital capacity percent predicted was a significant predictor of survival, and that the activity score in the SGRQwas not significantly related to mortality. CONCLUSIONS: There was no significant relationship between HRQL evaluated with the SGRQ and the subsequent mortality in IPF. The present negative result might suggest that HRQL is measuring an aspect other than one from physiological and functional impairment or disability.

The Local Structure and Metal-Insulator Transition in a Ba3Nb5-xTixO15 System.

The local structure of the filled tetragonal tungsten bronze (TTB) niobate Ba3Nb5-xTixO15 (x = 0, 0.1, 0.7, 1.0), showing a metal-insulator transition with Ti substitution, has been studied by Nb K-edge extended X-ray absorption fine structure (EXAFS) measurements as a function of temperature. The Ti substitution has been found to have a substantial effect on the local structure, that remains largely temperature independent in the studied temperature range of 80-400 K. The Nb-O bonds distribution shows an increased octahedral distortion induced by Ti substitution, while Nb-Ba distances are marginally affected. The Nb-O bonds are stiffer in the Ti substituted samples, which is revealed by the temperature dependent mean square relative displacements (MSRDs). Furthermore, there is an overall increase in the configurational disorder while the system with Nb 4d electrons turns insulating. The results underline a clear relationship between the local structure and the electronic transport properties suggesting that the metal-insulator transition and possible thermoelectric properties of TTB structured niobates can be tuned by disorder.

A survey on diarrhea and convenience of intake associated with a single-dose extended release formulation of azithromycin.

The development of a single-dose extended release formulation of azithromycin (AZ-SR) improves the adherence. However, gastrointestinal side effects such as diarrhea are frequent adverse drug reactions. The aim of the present study was to investigate the incidence of patient-reported in a diarrhea and the convenience of intake of AZ-SR in an Asian population. To assess the incidence of diarrhea and convenience of intake, patient-reported in a questionnaire about the incidence, onset, duration and severity of diarrhea, shape of stool, and patients' impression on taste. The drug was prepared and used in common with the hospital pharmacy and the community pharmacy. AZ-SR was prescribed in 96 outpatients, among whom 81 patients received the medicine and the questionnaire at the hospital pharmacy or one of five neighboring community pharmacies. The recovery of the questionnaire was 40.7%. Diarrhea occurred in 18 of 33 patients (54.5%), which was more frequent than in earlier reports, although the symptom was mild (grade 1-2) and occurred in most cases within 2 days. Approximately one third of patients reported inconvenience in taking the formulation in respect of the ease (36.4%), amount (42.4%), and unpleasant bitter taste (36.4%). We report here the importance of collaboration between hospital pharmacists and community pharmacists in providing accurate drug information, including the incidence of diarrhea, to patients receiving AZ-SR.

Coding characteristics of spiking local interneurons during imposed limb movements in the locust.

The performance of adaptive behavior relies on continuous sensory feedback to produce relevant modifications to central motor patterns. The femoral chordotonal organ (FeCO) of the legs of the desert locust monitors the movements of the tibia about the femoro-tibial joint. A ventral midline population of spiking local interneurons in the metathoracic ganglia integrates inputs from the FeCO. We used a Wiener kernel cross-correlation method combined with a Gaussian white noise stimulation of the FeCO to completely characterize and model the output dynamics of the ventral midline population of interneurons. A wide range of responses were observed, and interneurons could be classified into three broad groups that received excitatory and inhibitory or principally inhibitory or excitatory synaptic inputs from the FeCO. Interneurons that received mixed inputs also had the greatest linear responses but primarily responded to extension of the tibia and were mostly sensitive to stimulus velocity. Interneurons that received principally inhibitory inputs were sensitive to extension and to joint position. A small group of interneurons received purely excitatory synaptic inputs and were also sensitive to tibial extension. In addition to capturing the linear and nonlinear dynamics of this population of interneurons, first- and second-order Wiener kernels revealed that the dynamics of the interneurons in the population were graded and formed a spectrum of responses whereby the activity of many cells appeared to be required to adequately describe a particular stimulus characteristic, typical of population coding.

A simple assessment of dyspnoea as a prognostic indicator in idiopathic pulmonary fibrosis.

The prognosis in idiopathic pulmonary fibrosis (IPF) is poor. No therapy has been shown to prolong survival. The objective of this study was to examine the prognostic significance of dyspnoea in daily living at baseline in IPF using a simple assessment tool. 93 consecutive patients with IPF, who had undergone evaluation at diagnosis, were included. The level of dyspnoea was assessed using the modified Medical Research Council (MRC) scale. The relationship between data at baseline and survival was examined. A univariate Cox proportional-hazard model showed that forced vital capacity % predicted (hazard ratio (HR) 0.965, 95% CI 0.948-0.982; p<0.0001), diffusing capacity of the lung for carbon monoxide % predicted (HR 0.978, 95% CI 0.963-0.993; p = 0.0041), baseline arterial oxygen tension (HR 0.963, 95% CI 0.938-0.989; p = 0.0060) and modified MRC score (HR 2.402, 95% CI 1.495-3.858; p = 0.0003) were significantly predictive of survival. All variables of the 6-min walk test, including walk distance (HR 0.995, 95% CI 0.992-0.998; p = 0.0020), the lowest arterial oxygen saturation measured by pulse oximetry (S(p,O(2))) (HR 0.944, 95% CI 0.918-0.972; p<0.0001) and the Borg scale (HR 1.285, 95% CI 1.091-1.514; p = 0.0027), were also significant. With stepwise, multivariate Cox proportional analysis, the modified MRC score (HR 2.181, 95% CI 1.333-3.568; p = 0.0019) and the lowest S(p,O(2)) during the 6-min walk test (HR 0.952, 95% CI 0.924-0.981; p = 0.0014) were the most significant. Dyspnoea in daily living, assessed with the modified MRC scale at baseline, provides additional prognostic information for patients with IPF.

Pirfenidone in idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease without proven effective therapy. A multicentre, double-blind, placebo-controlled, randomised phase III clinical trial was conducted in Japanese patients with well-defined IPF to determine the efficacy and safety of pirfenidone, a novel antifibrotic oral agent, over 52 weeks. Of 275 patients randomised (high-dose, 1,800 mg x day(-1); low-dose, 1,200 mg x day(-1); or placebo groups in the ratio 2:1:2), 267 patients were evaluated for the efficacy of pirfenidone. Prior to unblinding, the primary end-point was revised; the change in vital capacity (VC) was assessed at week 52. Secondary end-points included the progression-free survival (PFS) time. Significant differences were observed in VC decline (primary end-point) between the placebo group (-0.16 L) and the high-dose group (-0.09 L) (p = 0.0416); differences between the two groups (p = 0.0280) were also observed in the PFS (the secondary end-point). Although photosensitivity, a well-established side-effect of pirfenidone, was the major adverse event in this study, it was mild in severity in most of the patients. Pirfenidone was relatively well tolerated in patients with IPF. Treatment with pirfenidone may decrease the rate of decline in VC and may increase the PFS time over 52 weeks. Additional studies are needed to confirm these findings.

Risk factors of acute exacerbation of idiopathic pulmonary fibrosis.

BACKGROUND: Although acute exacerbation (AE) of idiopathic pulmonary fibrosis (IPF) is a well known clinical condition, predicting risk factors remain unknown. We evaluated the frequency, risk factors and impact on survival of AE-IPF. METHODS: We retrospectively studied patients diagnosed with IPF based on the criteria of the ATS/ERS consensus statement and followed them for periods of more than 3 years except in dead cases. Initial characteristics including the level of dyspnoea, which was assessed with the modified Medical Research Council (MRC) scale, and decline of forced vital capacity (FVC) defined by at least 10% decline at 6 months, were evaluated as possible risk factors for AE. RESULTS: Seventy-four patients with IPF were studied. One-year, two-year, and three-year incidence of AE were 8.6%, 12.6%, and 23.9%, respectively. Multivariate analysis revealed that higher body mass index (BMI) [hazard ratio (HR), 1.20; 95% confidence interval (CI), 1.03-1.40], higher modified MRC scale [HR, 2.93; 95% CI, 1.46-5.85], and a decline in FVC at 6 mounths [HR, 0.97-2.60 (per mo); 95% CI, 1.01-7.45] were independent risk factors for AE-IPF. The causes of death were assessed to be AE in 20 of 57 expired patients. A stepwise multivariate Cox regression model evaluating AE-IPF, adjusted for %FVC and decline in FVC, demonstrated a statistically significant impact on overall survival [HR, 2.79; 95% CI, 1.59-4.88; p < 0.001]. CONCLUSION: These data suggest that initial high modified MRC scale, high BMI, and decline in FVC at 6 months were significant independent risk factors for AE-IPF. AE was an independent prognostic factor in IPF.

Chemical fragment arrays for rapid druggability assessment.

Incorporation of early druggability assessment in the drug discovery process provides a means to prioritize target proteins for high-throughput screening. We present chemical fragment arrays as a method that is capable of determining the druggability of a given target with low protein and compound consumption, enabling rapid decision making during early phases of drug discovery.

Health-related quality of life in patients with idiopathic pulmonary fibrosis. What is the main contributing factor?

The prognosis of patients with idiopathic pulmonary fibrosis (IPF) is generally considered to be poor. As the disease progresses, patients invariably become severely limited in their activities. Therefore, evaluating the health-related quality of life (HRQoL) in IPF patients is considered to be important. However, there have been few studies of this kind to date. We applied the St. George's Respiratory Questionnaire (SGRQ) to 41 consecutive IPF patients and examined various physiological variables to identify factors that were correlated with the HRQoL. Total lung capacity, transfer factor, arterial partial pressure of oxygen at rest, the lowest oxygen saturation during exercise test, and the baseline dyspnoea index (BDI) score were significantly correlated with the total SGRQ score. A similar tendency was observed in each component. Conversely, peak oxygen uptake, known as one of the important factors that determines HRQoL in chronic obstructive pulmonary disease (COPD), did not correlate with any SGRQ scores. In stepwise multiple regression analysis, the BDI score was selected as the only factor significantly contributing to the total SGRQ score. Dyspnoea was the most important factor determining HRQoL in IPF. The types of other variables that correlated with the HRQoL in IPF patients were different from those in COPD.

Aortic blood momentum--the more the better for the ejecting heart in vivo?

OBJECTIVES: The aim of the present study was to test two hypotheses: (1) the momentum of the blood flowing out of the left ventricle toward the aorta (inertia force) plays an important role in the initiation of decay and the maximum rate of decay (peak (-dP/dt)) of left ventricular pressure (P); (2) a normal heart itself generates the inertia force which enhances its function. METHODS: The contribution of the inertia force to (-dP/dt) was theoretically given as rho c alpha, where rho is the blood density, c the pulse wave velocity, and alpha the deceleration rate of aortic blood flow. The correlations of peak (-dP/dt) with rho c alpha and with the time constant (tau) of the pressure decay during isovolumic relaxation, which was considered to represent myocardial relaxation characteristics, were compared in seven dogs. We developed a method of grading the strength of the inertia force, using the phase loop of left ventricular pressure (dP/dt vs. P relation). The method was applied to the records of 25 patients with ischemic heart disease, from which high fidelity left ventricular pressure recordings were available. RESULTS: The correlation of peak (-dP/dt) with rho c alpha was much higher than with tau (0.75 vs. -0.46). 16 of the 25 patients showed evidence of the inertia force. However, other patients showed no inertia force. The strength of the inertia force showed a significant (P < 0.05) correlation with left ventricular end-diastolic pressure (r = -0.46), cardiac index (r = 0.62), stroke volume index (r = 0.69), ejection fraction (r = 0.46), and peak (-dP/dt) (r = 0.56). CONCLUSION: The inertia force of late systolic aortic flow contributed to ventricular relaxation in the normal heart.

Effect of thyrotropin-releasing hormone on cerebral blood flow in conscious rat.

The effect of thyrotropin-releasing hormone (TRH) was studied on local CBF (LCBF) in normal conscious rats. LCBF was measured by the autoradiographic [14C]iodoantipyrine method 5 min after TRH (5 mg/kg, i.v.) administration. TRH significantly increased LCBF in 22 of 33 brain regions. This increase of LCBF exceeded 100% of the control values in the cerebral cortices, whereas there was no significant increase in white matter or in some gray matter structures. The increase of CBF following TRH administration was abolished by pretreatment with indomethacin (5 mg/kg, i.v.). The mechanisms underlying the increase of CBF following TRH administration are discussed in relation to prostaglandin metabolism.

Vascular and metabolic reserve in Alzheimer's disease.

Vascular and metabolic reserve were analyzed in probable Alzheimer's disease (AD) and vascular dementia (VaD). Cerebral blood flow (CBF), cerebral blood volume (CBV), cerebral metabolic rate of oxygen (CMRO(2)), and oxygen extraction fraction (OEF) were measured quantitatively with positron emission tomography (PET). Vascular reactivity (VR) was also calculated by comparing the CBF during 5% CO(2) inhalation with the CBF during normal breathing. Vascular transit time (VTT) that was calculated as a ratio of CBV/CBF and VR reflect vasodilating capacity of the small resistance vessels, whereas OEF designates metabolic (oxygen-extraction) reserve in threatening brain ischemia. Significant increase in OEF was seen in the parieto-temporal cortex and both VTT and VR were preserved in AD patients. By constrast, there was no significant increase in OEF whereas VTT was prolonged and VR was markedly depressed in VaD patients. The increase of OEF and preserved VTT and VR seen in AD patients indicate the possible participation of vascular factors in the pathogenesis of AD perhaps at the capillary level.

A simple, two-color fluorescence detection method for membrane blotting analysis using alkaline phosphatase and horseradish peroxidase.

We have developed a one-step, two-color fluorescence detection method using simultaneously two fluorogenic substrates for both Southern and Western blots on nylon membranes. For this enzyme-mediated reporter system, a mixture of (i) 3-hydroxy-N-2'-biphenyl-2-naphthalenecarboxamide phosphate ester (HNPP), a substrate for alkaline phosphatase and (ii) N-(4-amino-5-methoxy-2-methylphenyl)benzamide (AMMB), a fluorogenic substrate for horseradish peroxidase was used. The reaction with these substrates produces blue (HNPP) and yellow (AMMB) fluorescent signals under ultraviolet light (302 nm). Therefore, this simple method allows the simultaneous visualization of two different targets on a single nylon membrane, e.g. nucleic acids or proteins.

Distribution and ultrastructure of synapses on a premotor local nonspiking interneuron of the crayfish.

Many premotor local nonspiking interneurons are involved in the control of the uropod movements of a crayfish. One of these interneurons was impaled intracellularly, characterized physiologically, and then labeled by intracellular horseradish peroxidase (HRP) injection to examine the distribution and ultrastructure of synapses. Depolarization of this interneuron by a current injection excited the closer motoneurons of the uropod and inhibited its opener motoneurons, but hyperpolarization had no effect. Input and output synapses are distributed all over the major branches and the finer neurites except for the main neurite (7-10 micron in diameter), which runs near the dorsal surface of the neuropil. Both types of synapse are located on the same neurite and are often intermingled in close proximity, often less than 1 micron apart. Presynaptic terminals of the interneuron contain round, clear vesicles that are densely packed in fine branches and spines. The number of synaptic vesicles associated with a particular output synapse was estimated to be about 2,000. No dense-cored granules are observed in the labeled neurites. Our results support the proposal that synaptic transmission in this class of interneurons of the crayfish can sometimes be restricted to a very small region of the branches and that, therefore, different regions of the interneuron can function independently.

Regional specialization in synaptic input and output in an identified local nonspiking interneuron of the crayfish revealed by light and electron microscopy.

Lateral inhibition of several mechanosensory interneurons in the crayfish terminal ganglion is mediated by a pair of identified local nonspiking interneurons called local directionally selective (LDS) interneurons. The ultrastructure and synaptic distribution of these interneurons were investigated by using intracellular labeling with horseradish peroxidase for electron microscopy. The LDS interneuron has bilateral, asymmetric arborizations. They are connected by a thick transverse neurite on which no synapses are made. The neurites on the side ipsilateral to the cell body are smooth and receive almost entirely input synapses. On the other hand, the contralateral neurites have prominent numerous swellings or varicosities from which many short fine spines arise, with intermingled input and output synapses. Both synapses, however, are not always associated with varicosities and spines. Presynaptic neurites of the LDS interneuron contain only round agranular synaptic vesicles in the vicinity of synaptic specializations. These morphological findings correlate well with the physiology of this interneuron: it is functionally polarized to receive input on one side (ipsilateral to the cell body) of the ganglion and convey it to the other side.

Decreased expression of the metastasis suppressor gene KAI1 in gastric cancer.

KAI1 was immunohistochemically detected in the lower part of fundic glands and intestinal metaplasia in non-cancerous gastric tissues, while only 11.0% (8/73) of cancerous tissues were shown to be positive. The relationship between various clinicopathological characteristics of patients with gastric cancer and KAI1 expression in their tumors was then analyzed to reveal that the incidence of positivity was 16.6% (8/48) of patients with stage Ia-IIIa and 0% (0/25) of patients with stage IIIb-IVb (P < 0.05) and that the incidence of peritoneal or hepatic metastasis tended to be lower in KAI1-positive tumors than in negative ones. These results suggest that decreased KAI1 expression may be related to the progression of gastric cancer.

7S collagen in bronchoalveolar lavage fluid of patients with adult respiratory distress syndrome.

To evaluate the disruption of the basement membrane in the pathogenesis of adult respiratory distress syndrome (ARDS), we measured the level of 7S collagen in the bronchoalveolar lavage (BAL) fluid of patients with ARDS and normal control subjects by using a radioimmunoassay method. Twelve of 14 patients with ARDS had evidence of 7S collagen in the BAL fluid, but no 7S collagen was detected in the BAL fluid of the controls. The mean 7S collagen concentration of the BAL fluid in patients with ARDS was 19.6 +/- 9.4 ng/ml. In patients with ARDS, the BAL levels of 7S collagen correlated strongly with neutrophil counts (r = 0.813; p less than 0.01) and with elastase-complex (r = 0.914; p less than 0.01). We conclude that 7S collagen may be an index of leukocyte-mediated lung injury in patients with ARDS, and detection of 7S collagen in BAL fluid is useful for evaluating the disruption of basement membrane.

Acute exacerbation in idiopathic pulmonary fibrosis. Analysis of clinical and pathologic findings in three cases.

We treated three patients with idiopathic pulmonary fibrosis who had an acute clinical exacerbation. We analyzed their clinical, radiographic, therapeutic, and pathologic findings. Their initial symptoms were influenza-like illness or cough with fever, and all had leukocytosis and elevation of C-reactive protein. Infectious events were ruled out by extensive bacteriologic and serologic examination. The patients' lung injury scores progressed rapidly to severe lung injury compatible with adult respiratory distress syndrome. Findings from bronchoalveolar lavage fluid showed marked neutrophilia and elevation of albumin concentrations. All patients showed various degrees of improvement following corticosteroid therapy. Histologic findings from open lung biopsy specimens showed both usual interstitial pneumonia (UIP) and organizing acute lung injury pattern. Whether these two forms of interstitial pneumonia (UIP and acute lung injury pattern) are variants of one disease or are unrelated and also the effectiveness of corticosteroid therapy on such conditions remain to be determined by further studies.

Emphysematous change in chronic asthma in relation to cigarette smoking. Assessment by computed tomography.

To evaluate the occurrence and the degree of emphysema in chronic asthma in relation to the effect of cigarette smoking, we examined 35 subjects with irreversible airway obstruction (17 nonsmokers and 18 smokers). We performed pulmonary function testing and CT scans on all subjects. The ES was assessed by a visual scoring system on CT scans. Between nonsmokers and smokers, there was a significant difference in the ES (p less than 0.05), but not in the FEV1, TLC, and Dsb/VA (expressed as percent predicted values). The ES was 2.3 +/- 4.7 percent (mean +/- SD) in nonsmoking subjects and 13.7 +/- 16.7 percent in smoking subjects. In all subjects the ES showed significant correlations with Dsb/VA (p less than 0.001) and pack-years of cigarette consumption (p less than 0.001) but did not show correlations with FEV1 and with TLC. We concluded that emphysema can occur in smoking asthmatic subjects because of the effect of cigarette smoking, and CT scans are useful for detecting this emphysematous change.

Carbon sources for D-lactate formation in rat liver.

Carbon sources for D-lactate formation were investigated in vitro using 6,000 x g supernatant of rat liver homogenate and by rat liver perfusion in situ. As carbon sources, L-threonine, glucose, glycerol, acetone, and acetoacetate were tested. Glycerol was the best substrate for D-lactate formation via methylglyoxal in rat liver. Glucose was the second most preferred substrate, while L-threonine, acetone, and acetoacetate were poor substrates for D-lactate formation. Glycerol was several times more effective than normal as a substrate of D-lactate in the supernatants of liver homogenates of diabetic and starved rats, while it was less effective as a substrate of L-lactate. The glycerol kinase [EC 2.7.1.30] activities in livers increased in the diabetic and starved states. These and other results can explain why the plasma concentration of D-lactate increases several-fold after running and why the D-lactate contents in plasma, liver, and skeletal muscle are markedly increases in diabetic and starved rats.