IκB kinase ß inhibitor IMD-0354 suppresses airway remodelling in a Dermatophagoides pteronyssinus-sensitized mouse model of chronic asthma.

BACKGROUND: Nuclear factor (NF)-κB is a transcription factor that regulates cytokine and chemokine production in various inflammatory diseases, including bronchial asthma. IκB kinase (IKK) ß is important for NF-κB activation in inflammatory conditions, and is possibly related to airway remodelling. Thus, inhibition of the IKKß-NF-κB pathway may be an ideal strategy for the management of airway remodelling. OBJECTIVE: We examined the effects of a newly synthesized IKKß inhibitor, IMD-0354, in a chronic allergen exposure model of bronchial asthma in mice. METHODS: A chronic mouse model was generated by challenge with house dust mite antigen (Dermatophagoides pteronyssinus). IMD-0354 was administrated intraperitoneally in therapeutic groups. Lung histopathology, hyperresponsiveness and the concentrations of mediators and molecules in supernatants of lung homogenates were determined. RESULTS: NF-κB activation was inhibited by prolonged periods of IMD-0354 administration. IMD-0354 reduced the numbers of bronchial eosinophils. IMD-0354 also inhibited the pathological features of airway remodelling, including goblet cell hyperplasia, subepithelial fibrosis, collagen deposition and smooth muscle hypertrophy. Inhibition of these structural changes by IMD-0354 was the result of the suppressing the production and activation of remodelling-related mediators, such as TGF-ß, via inhibition of IKKß. IMD-0354 inhibited IL-13 and IL-1ß production, and it restored the production of IFN-γ. It also ameliorated airway hyperresponsiveness. CONCLUSION: IKKß plays crucial roles in airway inflammation and remodelling in a chronic mouse model of asthma. A specific IKKß inhibitor, IMD-0354, may be therapeutically beneficial for treating airway inflammation and remodelling in chronic asthma.

A 718-kb DNA sequence of the Escherichia coli K-12 genome corresponding to the 12.7-28.0 min region on the linkage map.

The 718,122 base pair sequence of the Escherichia coli K-12 genome corresponding to the region from 12.7 to 28.0 minutes on the genetic map is described. This region contains at least 681 potential open reading frames, of which 277 (41%) have been previously identified, 147 (22%) are homologous to other known genes, 139 (20%) are identical or similar to the hypothetical genes registered in databases, and the remaining 118 (17%) do not show a significant similarity to any other gene. In this region, we assigned a cluster of cit genes encoding multienzyme citrate lyase, two clusters of fimbrial genes and a set of lysogenic phage genes encoding integrase, excisionase and repressor in the e14 genetic element. In addition, a new valine tRNA gene, designated valZ, and a family of long directly repeated sequences, LDR-A, -B and -C, were found.

Virtual cancer image data warehouse.

We previously developed a system with which we have created more than 100 virtual cancer images from CT or MR data of individual patients with cancer (Cancer Edutainment Virtual Reality Theater: CEVRT). These images can be used to help explain procedures, findings, etc. to the patient, to obtain informed consent, to simulate surgery, and to estimate cancer invasion to surrounding organs. We recently developed a web-based object-oriented database both to access these cancer images and to register medical images at international research sites via the Internet. In this report, we introduce an international medical VR data warehouse created using an object-oriented database.

Left ventricular ejection time measured by finger-tip plethysmography in healthy young Japanese. Its correction for heart rate.

Finger-tip plethysmograms were recorded photoelectrically on 200 young males and females each. The relation between the left ventricular ejection time (ET) and the preceding heart rate (HR) and a method for correcting ET for the heart rate were studied. The values calculated by the formula ET/S-S or ET/square root S-S varied with the HR, so these formulae cannot be used for correcting the ET for HR. Thus from the relationship between ET and HR, a formula for converting the measured ET to the ET at an HR OF 70, I.E. ETc, was deduced. ETc equals ET + HR - 70. This formula can be used for both sexes of Japanese juveniles and the values obtained by it can be directly compared, irrespective of the HR.

Aldosterone responsiveness to angiotensin II after sodium restriction in subjects with low renin essential hypertension.

Plasma aldosterone (PA) responses to sodium restriction (25 mEq sodium/day for 4 days) and to graded angiotensin II (AII) infusions (2, 4 and 8 ng/kg/min each for 30 min) during a low sodium intake were studied in 14 subjects with low renin essential hypertension (LREH) versus 16 normotensive subjects. The PA response to sodium restriction in relation to changes in plasma renin activity (PRA) was estimated by the ratio of PA increment to PRA increment after sodium restriction (delta PA/delta PRA). In 8 of 14 LREH subjects, whose delta PA/delta PRA ratios were normal, the PA responses to the graded AII doses were similar to those in the normotensive subjects. However, in the remaining 6 LREH subjects whose delta PA/delta PRA ratios were high the PA responses to the graded AII doses were greater. Apparently some LREH subjects, whose delta PA/delta PRA ratios after sodium restriction were high, have an abnormally enhanced aldosterone responsiveness to AII under the condition of low sodium intake.

Effects of diltiazem Hydrochloride (CRD-401) on renal hemodynamics of dogs.

The effect of d-3-acetoxy-cis-2,3-dihydro-5-[2-(dimethylamino)ethyl]-2-(p-methoxyphenyl)-1,5-benzothiazepine-4(5H)one hydrochloride (ditiazem hydrochloride, CRD-401) on renal hemodynamics was investigated in 18 mongrel adult dogs, and the following results were obtained. 1. Renal blood flow (RBF) was significantly increased following i.v. injection of 100 microgram/kg of CRD-401, in spite of decreased ao-tic blood pressure. Moreover the same dose of the drug elicited greater increase in RBF while the renal arteries were perfused at a constant pressure in order to prevent the decrease in systemic blood pressure from affecting RBF. These results suggest that CRD-401 has a vasodilatory action on the renal arteries. 2. The increasing rate of RBF and decreasing rate of renal vascular resistance (RVR) after injection of the drug into the renal artery at the dose level of 3 microgram/kg were found to diminish by pretreatment with hexamethonium (C6) before CRD-401. The vasodilating effect of CRD-401 on the renal arteries was therefore assumed to be more prominent in a state of renal arterial constriction. 3. RBF and RVR were increased and decreased, respectively, in proportion to the doses of CRD-401 ranging from 3 to 100 microgram/kg, the vasodilating action of CRD-401 on the renal arteries increased dose-dependently.

[Total blood volume in essential and secondary hypertension].

To study the role of volume factors in the pathogenesis of hypertension, total blood volume (TBV) was determined in 43 patients with essential hypertension, 10 with primary aldosteronism, 5 with Cushing's syndrome, 5 with renovascular hypertension and 23 age-matched normotensives. The radioisotope (131I) labeled plasma tracer technique was employed under conditions of constant sodium intake (200mEq/day). The TBV values obtained were expressed as % normal against the predicted values according to the formulae of Fujita and his co-workers. The results were as follows: (1) TBV was increased in patients with primary aldosteronism. (2) In essential hypertensive patients, with either normal or low plasma renin activity, TBV was normal. (3) There was no increment of TBV in patients with Cushing's syndrome. These results suggest that expanded intravascular volume plays a major role in the mechanism of hypertension with suppressed plasma renin activity in primary aldosteronism, whereas other unknown factors may be related to the causes of hypertension in patients with essential hypertension and Cushing's syndrome.

Hemodynamic effects of [Sar1, Ile8] AII, an angiotensin II analog, in the renin subgroups of essential hypertension.

Hemodynamic effects of [Sar1, Ile8] AII, an angiotensin II analog, were studied in 30 patients with essential hypertension, who were subdivided into 11 low renin, 10 normal renin and 9 high renin groups according to low, normal and high PRA values both before and after furosemide administration (80 mg, orally) plus 4 h of ambulation, respectively. [Sar1, Ile8] AII infusion (600 ng/kg/min) produced significant increases in mean blood pressure (MBP) and total peripheral resistance index (TPRI) in normal renin and low renin groups and significant decreases in MBP and TPRI in high renin group, while the cardiac index and heart rate remained unchanged during the infusion in these three groups. Change in MBP at 30 min of [Sar1, Ile8] AII infusion correlated significantly with alteration in TPRI in 23 patients with essential hypertension, who completed the 30-min infusion. The response of both MBP and TPRI to [SAR1, Ile8] AII also correlated significantly with basal PRA. These results suggest that blood pressure response to [SAR1, Ile8] AII in essential hypertension is primarily due to alteration in total peripheral resistance and that direction and amplitude of the response of both MBP and TPRI are practically dependent on basal PRA levels.

Catalytically inactive lecithin: cholesterol acyltransferase (LCAT) caused by a Gly 30 to Ser mutation in a family with LCAT deficiency.

Plasma lecithin:cholesterol acyltransferase (LCAT) plays an important role in early steps of reverse cholesterol transport, i.e., cholesterol efflux from peripheral tissues and cholesterol esterification in HDL. However, structural and functional relationships of LCAT have not been fully elucidated. We described a missense mutation of Gly 30-to-Ser in a patient with classical LCAT deficiency. The proband was homozygous for the mutation and had a very low level of HDL cholesterol (2 mg/dl), with a half of normal LCAT mass (2.75 micrograms/ml), but no detectable or very low LCAT activity in endogenous and exogenous substrate assays. Both his mother and sister were heterozygous for the mutation, and had slightly decreased levels of HDL cholesterol (34 and 36 mg/dl, respectively). Transient expression study using COS cells indicated that mutant cDNA produces similar amounts of media protein as compared to wild type, but no detectable LCAT activity. The missense mutation may result in a near-native conformation without large effects on cellular secretion but a catalytically defective protein. Thus, the N-terminal domain appears crucial for enzymatic activity, in addition to the catalytically active consensus sequence of Gly179 to Gly183 and a putative sterol binding domain of Glu154 to Lys173.