Tumour necrosis factor α augments the inhibitory effects of CTLA-4-Ig on osteoclast generation from human monocytes via induction of CD80 expression.

Cytotoxic T lymphocyte antigen-4-immunoglobulin (CTLA-4-Ig) exerts anti-rheumatic action via negative regulation of the co-stimulation process between antigen-presenting cells and T cells. CTLA-4-Ig also binds to CD80/CD86 on monocytes of osteoclast precursors. However, little is known about the effect of CTLA-4-Ig on osteoclastogenesis in rheumatoid arthritis (RA). In this study we evaluated the effects of CTLA-4-Ig on osteoclast generation from human blood monocytes (PBM) and rheumatoid synovial fluid monocytes (RSFM). Highly purified monocytes were cultured with receptor activator of nuclear factor kappa-B ligand (RANKL) and macrophage colony-stimulating factor (M-CSF) in the presence of CTLA-4-Ig. CTLA-4-Ig inhibited RANKL-induced osteoclast generation in PBM and RSFM, as determined by tartrate-resistant acid phosphatase (TRAP) staining and bone resorption assay using osteo assay surface plates. In addition, CTLA-4-Ig reduced the gene and protein expressions of nuclear factor of activated T cells, cytoplasmic 1 (NFATc1) and cathepsin K during osteoclastogenesis. Furthermore, CTLA-4-Ig significantly inhibited cell proliferation during osteoclastogenesis. Interestingly, the gene expression of indoleamine 2,3-dioxygenase-1, an inducer of apoptosis, was enhanced by CTLA-4-Ig. We next examined the effect of tumour necrosis factor (TNF)-α, a major inflammatory cytokine in rheumatoid synovium, on the expression of CD80 and CD86 by flow cytometric analysis. TNF-α potently induced the surface expression of CD80, which is known to have much higher affinity to CTLA-4-Ig than CD86, and this induction was observed at mRNA levels. Interestingly, freshly prepared rheumatoid synovial monocytes also expressed CD80 as much as TNF-α-treated PBM. Furthermore, TNF-α enhanced CTLA-4-Ig-induced inhibition of osteoclastogenesis and cell proliferation. Taken together, the TNF-α-induced CD80 may augment CTLA-4-Ig-induced inhibition of osteoclastogenesis, suggesting that CTLA-4-Ig potently inhibits osteoclast differentiation and protects bone destruction in rheumatoid inflamed joints.

Increased phosphatidylcholine concentration in saliva reduces surface tension and improves airway patency in obstructive sleep apnoea.

Surface tension may have important role for maintaining upper airway patency in patients with obstructive sleep apnoea. It has been demonstrated that elevated surface tension increases the pharyngeal pressures required to reopen the upper airway following collapse. The aim of the study was to evaluate the associations between the concentrations of endogenous surfactants in saliva with indices of upper airway patency in obstructive sleep apnoea. We studied 20 male patients with obstructive sleep apnoea (age: 60·3 ± 10·3 years; BMI: 25·9 ± 4·6 kg m(-2); AHI: 41·5 ± 18·6 events h(-1)). We obtained 100-µL samples of saliva prior to overnight polysomnographic sleep study. The surface tension was determined using the pull-off force technique. The concentration of phosphatidylcholine (PC) was evaluated by liquid chromatography-mass spectrometry (LC-MS/MS). Regression analysis between apnoea, hypopnoea and apnoea/hypopnoea indices and the ratio of hypopnoea time/total disordered breathing time (HT/DBT) with surface tension and PC were performed. P < 0·05 was considered significant. The mean saliva surface tension was 48·8 ± 8·0 mN m(-1) and PC concentration was 15·7 ± 11·1 nM. The surface tension was negatively correlated with the PC concentration (r = -0·48, P = 0·03). There was a significant positive correlation between surface tension with hypopnoea index (r = 0·50, P = 0·03) and HT/DBT (r = 0·6, P = 0·006), but not apnoea or apnoea/hypopnoea index (P > 0·11). Similarly, PC concentration negatively correlated with hypopnoea index (r = -0·45, P = 0·04) and HT/DBT (r = -0·6, P = 0·004), but not with apnoea index or AHI (P > 0·08). An increase in salivary PC concentration may increase upper airway patency in obstructive sleep apnoea through a reduction in surface tension.

The mandible advancement may alter the coordination between breathing and the non-nutritive swallowing reflex.

The coordination between nasal breathing and non-nutritive swallowing serves as a protective reflex against potentially asphyxiating material, i.e. saliva and secretions, entering the respiratory tract. Although this protective reflex is influenced by positional changes in the head and body, the effect of mandible position on this reflex is not fully understood. We examined the effect of mandible advancement associated with mouth opening on the coordination between nasal breathing and non-nutritive swallowing induced by continuous infusion of distilled water into the pharyngeal cavity. The combination of mandible advancement and mouth opening increased the duration of swallowing apnoea and submental electromyographic burst duration. When the mandible was advanced with the mouth open, the duration of swallowing apnoea increased significantly compared with the centric position (0.79 +/- 0.23 vs. 0.64 +/- 0.12 s, P < 0.05, n = 12), and the duration of submental electromyographic activity increased significantly (2.11 +/- 0.63 vs. 1.46 +/- 0.25 s, P < 0.05, n = 12). Mandible advancement with mouth opening altered the respiratory phase resetting during swallowing and the timing of swallow in relation to respiratory cycle phase. We conclude that mandible re-positioning may strongly influence the coordination between nasal breathing and non-nutritive swallowing by altering respiratory parameters and by inhibiting movement of the tongue-jaw complex.

Enhancing the efficacy of psychoeducational interventions for paediatric patients in a randomised controlled trial: methodological considerations.

AIM: This paper described a case study of a randomised controlled trial with the aim to illuminate how the intervention described takes into account the important methodological considerations for enhancing the efficacy of psychoeducational interventions for paediatric patients. BACKGROUND: Many nursing intervention studies commit a Type II error despite the fact that the intervention is effective. Lack of attention given to the threats of validity of an intervention study may lead to inaccurate inference about the efficacy of the intervention study, thereby precluding any definitive conclusions being drawn. DESIGN: A case study of a randomised controlled trial was described. METHOD: Two hundred and three Hong Kong Chinese children, admitted for elective surgery, were invited to participate in the study. By using a simple complete randomisation method, 97 children were assigned to the experimental group and received therapeutic play intervention and 106 children were assigned to the control group and received routine information preparation. RESULTS: Children received preoperative therapeutic play intervention experienced lower anxiety levels, fewer negative emotions and lower heart rates and mean arterial blood pressures. CONCLUSION: This case study illustrates that the more a measure is sensitive to differentiate between the experimental and control groups, the greater the likelihood of documenting intervention efficacy. Besides, the timing of measuring a dependent variable that matches with peak response to an intervention is crucial in evaluating the efficacy of an intervention. Additionally, outcome measures that are sensitive enough to differentiate between the experimental and control groups are extremely important to ensure greater accuracy in evaluating the efficacy of psychoeducational interventions. RELEVANCE TO CLINICAL PRACTICE: It is anticipated that designing an effective psychoeducational intervention research design can facilitate the development of holistic and quality care in preparing children for hospitalisation.

The effect of tooth clenching on the sensory and pain perception in the oro-facial region of symptom-free men and women.

The aim of this study was (i) to examine the effect of light tooth contact as in diurnal tooth clenching on the tactile detection threshold (TDT), the filament-prick pain detection threshold (FPT) and the pressure pain threshold (PPT) in the oro-facial region and (ii) to examine the possible gender difference in this effect on the tactile and pain perception. Twenty healthy volunteers participated. The TDT and the FPT were measured by means of Semmes-Weinstein monofilaments, on the cheek skin (CS) overlying the masseter muscles (MM) and on the skin overlying the palm side of the thenar skin (TS). The PPT was measured at the central part of the MM using a pressure algometer. Each parameter was measured before and after keeping light tooth contact for 5 min (session 1) and after keeping the jaw relaxed for 5 min (session 2) as a control. Although there were no significant session effects on any of the parameters, there were significant effects of experimental condition on the TDT in both men and women (P < 0.001). Men had a significant higher FPT of the left CS (P < 0.05) and TS (P < 0.01) and a significant higher PPT of the MM than women (P < 0.001). These results illustrate that sensitivity to pain (FPT, PPT) was higher in women than in men. Although there were no significant gender differences in habituation of sensory perception, the increase of TDT after clenching/no clenching was larger in women, which warrants further study.

[Multiple recurrence of cardiac myxoma in a Carney complex patient 4 years after the first operation].

Carney complex is a rare syndrome which includes cardiac myxoma, hyperactive endocrine neoplasm, spotty pigmented skin, and extracardiac myxomatous tumors. We report a case of a 26-year-old woman with Carney complex in whom recurrent multiple cardiac myxomas were resected 4 years after the first operation for left atrial (LA) myxoma. She had a history of left adrenalectomy in 1997 for Cushing syndrome due to primary pigmented nodular adrenocortical disease (PPNAD). In February 2001, she was diagnosed with Carney complex because of evidence of LA myxoma, her spotty pigmented skin lesions, her past history and family history of cardiac myxoma in her mother. Then, LA myxoma was successfully resected through the superior trans-septal approach and has been followed-up by ultrasound cardiography (UCG) every 6-month after discharge. In January 2005, UCG revealed 2 masses in the LA and the right ventricle outflow tract. The 2nd surgery was performed in February 2005. We found the 3rd myxoma during surgery, resembling a flat polyp in the LA just at the inflow of the right upper pulmonary vein. All 3 myxomas were successfully resected. Sixteen months after the 2nd operation, she has been doing well without any sign of recurrence of myxoma.

Effect of mandibular position on upper airway collapsibility and resistance.

It has been proposed that advancement of the mandible is a useful method for decreasing upper airway collapsibility. We carried out this study to test the hypothesis that mandibular advancement induces changes in upper airway patency during midazolam sedation. To explore its effect, we examined upper airway pressure-flow relationships in each of 4 conditions of mouth position in normal, healthy subjects (n = 9). In the neutral position, Pcrit (i.e., critical closing pressure, an index of upper airway collapsibility) was -4.2 cm H(2)O, and upstream resistance (Rua) was 21.2 cm H(2)O/L/sec. In the centric occlusal position, Pcrit was -7.1 cm H(2)O, and Rua was 16.6 cm H(2)O/L/sec. In the incisor position, Pcrit was significantly reduced to -10.7 cm H(2)O, and Rua was significantly reduced to 14.0 cm H(2)O/L/sec. Mandibular advancement significantly decreased Pcrit to -13.3 cm H(2)O, but did not significantly influence Rua (22.1 cm H(2)O/L/sec). We conclude that the mandibular incisors' position improved airway patency and decreased resistance during midazolam sedation.

High prevalence of small dense LDL in diabetic nephropathy is not directly associated with kidney damage: a possible role of postprandial lipemia.

To determine whether high prevalence of small dense low-density lipoprotein (LDL) in non-insulin-dependent diabetes (NIDDM) with nephropathy is directly associated with kidney damage, we measured LDL particle size by non-denaturing 2-16% gradient polyacrylamide gel electrophoresis in non-diabetic patients with primary renal disease and compared the results to particle size in NIDDM patients with diabetic nephropathy. The average LDL particle diameter was significantly smaller in patients with diabetic nephropathy (245+/-3 A mean +/- SEM) compared to the controls (263+/-1 A), diabetics without nephropathy (257+/-2 A), patients with primary renal disease (254+/-2 A) or non-diabetic patients treated with hemodialysis (HD) (260+/-1 A). The incidence of small LDL (mean diameter is < or =255 A) was remarkably increased in diabetic nephropathy (67%) compared to diabetes without nephropathy (27%), patients with renal disease (24%), HD patients (15%) and controls (10%). LDL size in patients with primary renal disease was significantly smaller than those in controls. However, because there was an excellent correlation between LDL size and plasma triglyceride (TG) levels, when hypertriglyceridemic subjects (TG >1.7 mM) were excluded, no difference of LDL size was observed between the renal disease group (260+/-2 A) and the control group (264+/-1 A). On the other hand, even when hypertriglyceridemic subjects were excluded, LDL size was still smaller in diabetic nephropathy (250+/-4 A). We performed an oral fat load test in normotriglyceridemic subjects (fasting TG <1.7 mM) of control, diabetes with and without nephropathy and primary renal disease. The TG responses in plasma and TG-rich-lipoprotein (TRL) (d <1.006) after the oral fat load were significantly greater in NIDDMs with nephropathy compared to controls or NIDDMs without nephropathy, while such a marked postprandial lipemia was not observed in patients with primary renal disease. In these fasting normotriglyceridemic subjects, LDL size was significantly inversely correlated with postprandial TG responses, which is totally independent from fasting TG levels. These results suggest that high prevalence of small dense LDL in NIDDM patients with nephropathy is not directly associated with kidney damage. Postprandial lipemia may play an important role in reducing LDL particle size in these patients.

The effect of atorvastatin on serum lipids and lipoproteins in patients with homozyous familial hypercholesterolemia undergoing LDL-apheresis therapy.

The efficacy of atorvastatin, a new hydroxymethylglutaryl (HMG)-CoA reductase inhibitor, in reducing serum lipid levels, modifying lipoprotein composition, and suppressing cholesterol synthesis was evaluated in patients with homozygous familial hypercholesterolemia (homozygous FH) undergoing LDL-apheresis therapy. Atorvastatin was given in escalating doses (10, 20, and 40 mg/day) to nine patients with homozygous FH. Five of nine patients responded well to atorvastatin; four of these patients were receptor-defective and the remaining one was receptor-negative. The change in LDL-cholesterol in the receptor-defective patients averaged -20.6% compared to the baseline level at the highest dose of atorvastatin. Of five receptor-negative type patients, only one showed good response to atorvastatin therapy with a LDL-cholesterol reduction of 14.9%. Although the other four receptor-negative patients did not show a change in LDL-cholesterol, all of them exhibited a considerable increase in HDL-cholesterol. All patients showed reduced urinary excretion of mevalonic acid, suggesting that atorvastatin decreases LDL-cholesterol by inhibiting cholesterol biosynthesis even where LDL-receptor activity is not present. Atorvastatin also decreased serum triglycerides in both receptor-negative and defective patients, especially in the latter. As cholesterol level rebounds quickly after each apheresis procedure, a combination therapy using atorvastatin and apheresis may increase the efficacy of the apheresis treatment, improving cost-benefit effectiveness by reducing the frequency of the apheresis treatment.

Propofol produces anticonflict action by inhibiting 5-HT release in rat dorsal hippocampus.

We examined the effect of propofol, an injectable anesthetic agent on conflict behavior in a Vogel type conflict test and on release of serotonin (5-hydroxytryptamine, 5-HT) in the dorsal hippocampus using an in vivo microdialysis method in rats. Propofol (20 and 40 mg/kg, i.p.) dose-dependently suppressed elevated 5-HT release normally seen in a conflict situation and concomitantly attenuated conflict behavior. These findings suggest that propofol exerts an antianxiety action by inhibiting 5-HT neuronal activity in the dorsal hippocampus.

Role of hepatic lipase in intermediate-density lipoprotein and small, dense low-density lipoprotein formation in hemodialysis patients.

BACKGROUND: It has been reported that remnant lipoproteins and small, dense low-density lipoproteins (LDLs) are risk factors for cardiovascular disease. To determine whether these risk factors are present in hemodialysis (HD) patients who are suffering from a high incidence of atherosclerotic vascular disease, we measured concentrations of remnant lipoproteins and LDL particle diameter in HD patients and compared these with controls. We also measured lipoprotein lipase (LPL) and hepatic triglyceride lipase (HTGL) that play important roles in the generation of remnant lipoproteins and small, dense LDL, and we correlated these changes with plasma lipoprotein abnormalities in HD patients. METHODS: Lipoproteins were separated by ultracentrifugation. Apoprotein B in very low-density lipoprotein (VLDL), and intermediate-density lipoprotein (IDL) fractions were measured by a sensitive enzyme-linked immunosorbent assay method. The average LDL particle diameter was measured by gradient gel electrophoresis. RESULTS: Plasma triglyceride, total cholesterol, and high-density lipoprotein (HDL) cholesterol concentrations were comparable between HD patients and controls, whereas LDL cholesterol was significantly lower in HD patients. The average LDL particle diameter was not significantly different between HD patients and controls. LDL particle diameter was inversely related to plasma triglyceride concentrations in all of the subjects. VLDL triglyceride, VLDL cholesterol, and VLDL apoprotein B were comparable between HD patients and controls. IDL triglyceride, IDL cholesterol, and IDL apoprotein B concentrations were all significantly increased in HD patients compared with those in controls. LPL mass was not altered, but HTGL activity was significantly decreased in HD patients. The HTGL activity was inversely related to IDL concentrations. CONCLUSIONS: These results suggest that a prominent characteristic of lipoprotein abnormalities in HD patients is a marked increase in IDL particle number. In addition, small, dense LDL is not associated with uremic dyslipidemia. Because HTGLs promote the conversion from IDL to LDL and the generation of lipid-poor LDL, a decrease in HTGL activity may contribute to the accumulation of IDL particle and may prevent small, dense LDL formation in HD patients.

Two-dimensional jaw tracking and EMG recording system implanted in the freely moving rabbit.

A system for simultaneously recording mandibular position in the sagittal plane together with masticatory muscle activity was designed and tested in rabbits. Two small magnetic sensors were implanted in the maxillary bone and a powerful magnet made of a rare earth metal attached to the mandibular central incisors. The magnetic sensors detected the mandibular movements in the sagittal plane by movement of the magnet. Masseter EMG was recorded by fine wire electrodes and amplified by a specially designed amplifier. The necessary preamplifiers were assembled as an integrated circuit (IC) chip in a small housing. The signals from the preamplifier were then passed through a signal processing unit and taped on an instrumentation tape. The system was applied to the freely moving rabbit supplied with food and water during the night. It worked without any trouble for more than 24 h. Since the implanted magnetic sensors were stable for more than 4 months, long-term recording could be done by merely reimplanting the magnet, the cables and the EMG electrodes, which was simple.

Conflict situation increases serotonin release in rat dorsal hippocampus: in vivo study with microdialysis and Vogel test.

The release of serotonin (5-hydroxytryptamine, 5-HT) in the dorsal hippocampus was measured using an in vivo microdialysis method in rats subjected to the Vogel type conflict test. The conflict situation significantly increased 5-HT release in the dorsal hippocampus. Midazolam (0.75 and 1.5 mg/kg i.p.) suppressed the dosage-dependently this increased 5-HT release, an inhibition closely associated with the attenuation of conflict behavior. These findings suggest that the activation of serotonergic neuronal activity in the dorsal hippocampus is linked to mediation of anxiety-related behavior.

Mouth-opening increases upper-airway collapsibility without changing resistance during midazolam sedation.

Sedative doses of anesthetic agents affect upper-airway function. Oral-maxillofacial surgery is frequently performed on sedated patients whose mouths must be as open as possible if the procedures are to be accomplished successfully. We examined upper-airway pressure-flow relationships in closed mouths, mouths opened moderately, and mouths opened maximally to test the hypothesis that mouth-opening compromises upper-airway patency during midazolam sedation. From these relationships, upper-airway critical pressure (Pcrit) and upstream resistance (Rua) were derived. Maximal mouth-opening increased Pcrit to -3.6 +/- 2.9 cm H2O compared with -8.7 +/- 2.8 (p = 0.002) for closed mouths and -7.2 +/- 4.1 (p = 0.038) for mouths opened moderately. In contrast, Rua was similar in all three conditions (18.4 +/- 6.6 vs. 17.7 +/- 7.6 vs. 21.5 +/- 11.6 cm H2O/L/sec). Moreover, maximum mouth-opening produced an inspiratory airflow limitation at atmosphere that was eliminated when nasal pressure was adjusted to 4.3 +/- 2.7 cm H2O. We conclude that maximal mouth-opening increases upper-airway collapsibility, which contributes to upper-airway obstruction at atmosphere during midazolam sedation.

Variation of the jaw-opening reflex during spontaneous mastication in rabbits.

To understand the modulation of periodontal mechanoreceptor activity on mastication, the jaw-opening reflex (JOR) evoked by electrical stimulation of the inferior alveolar nerve (IAN) was studied during chewing in freely behaving rabbits. Spontaneous chewing movements were intact from the IAN stimulation below two times the threshold (T) which was measured at rest. As the stimulus intensity was increased to more than 2.5 T, the amplitude of the masseter activity decreased or it was abolished; however, the chewing rhythm was still maintained up to 3.0 T. When the low-threshold primary afferents were tested while the rabbit chewed pellets rhythmically, the amplitude in the JOR was inhibited below the prior control level. The inhibitory effect on the JOR was larger in the opening phase than that in the closing phase. In conclusion, the JOR was tonically depressed during the masticatory cycle and the inhibition of the JOR was rhythmically modulated in a phase-linked manner that was larger in the opening phase than in the closing phase.

CD8+ lymphocyte infiltration and apoptosis in hepatocellular carcinoma.

AIMS: Tumour-infiltrating lymphocytes (TILs) play a role in local anti-tumour immunity. Tumour cells may escape from immune surveillance by expressing RCAS1, a receptor-binding cancer antigen expressed on SiSo cells, which inhibits T cell growth. In this study, the correlation between the density of CD8+ TILs, tumour cell apoptosis, and tumour RCAS1 expression was investigated in hepatocellular carcinoma (HCC). METHODS: We obtained tissues from 60 patients with surgically resected HCCs. CD8+ TILS, apoptotic cancer cells, and RCAS1 expressing cancer cells were identified by immunohistochemistry. RESULTS: The density of CD8+ T cells in tumours (mean: 9.5/HPF, HPF: high power field) was significantly less than in non-cancerous hepatic lobules (17.8/HPF, p<0.001) and in relation to the progression of tumour stage. The density of CD8+ T cells in tumours positively correlated with the occurrence of tumour cell apoptosis, but did not correlate with RCAS1 protein expression. CONCLUSIONS: CD8+ TILs may play a role in the occurrence of tumour cell apoptosis in HCC, but CD8+ TILs may not be controlled by RCAS1 in HCC.

Klinefelter's syndrome accompanied by mixed connective tissue disease and diabetes mellitus.

We report a rare case of Klinefelter's syndrome (KS) with mixed connective tissue disease (MCTD), diabetes mellitus (DM) and several endocrine disorders. A 57-year-old man presented with polyarthritis and tapering fingers with Raynaud's phenomenon on admission. In addition to a karyotype of 47, XXY, a marked restrictive change in respiratory functional test, a myogenic pattern in electromyogram, the positive tests for anti-RNP antibody indicated that this was a case of KS complicated with MCTD. The patients also presented DM with insulin resistance, hyperprolactinemia, slight primary hypothyroidism and hypoadrenocorticism. The mechanism for these coincidences remains to be elucidated.

Noxious stimulation reduces blood pressure but not flow in the internal carotid artery as measured in rabbits.

The purpose of this study was to examine effects on blood flow by alteration of blood pressure resulting from noxious stimuli. The experiment was carried out in anesthetized and paralyzed rabbits. Blood pressure was measured through a teflon catheter inserted in the common carotid artery (CCA). Blood flow at the CCA, internal carotid artery (ICA), or external carotid artery (ECA) was measured using an electromagnetic flowmeter placed at the CCA. The effects of pinching and electrical stimuli upon the blood pressure and flow were tested. Blood pressure at all three arteries decreased transiently from these noxious stimulations. There were no statistical changes in the blood flows respectively. However, different mechanism could exist between ECA and ICA because blood flow of ECA was decreased and that of ICA was increased or had no change. We concluded that vascular resistance reduction in the ICA against the arterial pressure decrement produced by noxious stimuli may be a control mechanism to keep cerebral blood flow constant. In contrast, there may be no such mechanism in the ECA circulation.

[A case of wide-spread emphysema following the extraction of mandibular third molar under intravenous sedation].

A 45 year-old male underwent lower left third molar extraction under intravenous sedation. During the surgical extraction of the mandibular left impacted third molar using a high-speed air-turbine drill, the patient complained of compression at the level of the right breast without any abnormal vital signs. Radiological investigation and CT scan showed a picture of bilateral, subcutaneous and mediastinal emphysema involving the bilateral face, neck and pectoral area. Following the antibiotic therapy, the drainage was performed through bilateral pectoral incisions by thoracic surgery. The patient recovered within two days and underwent the completion of this surgery under general anesthesia one month later.

Clinical effect of the anti-platelet drug, dilazep dihydrochloride, in patients at the microalbuminuric stage of diabetic nephropathy--a multi-center study.

Clinical effects of an anti-platelet drug (dilazep dihydrochloride) in the microalbuminuric stage of diabetic nephropathy were investigated in a multi-center study. Thirty-seven patients with at the microalbuminuric stage of diabetic nephropathy were examined in the present study. They were administered 300 mg/day of dilazep dihydrochloride (Comelian-Kowa) orally for 6 months. Mean values of albuminuria after the administration of dilazep dihydrochloride were significantly decreased compared with the pre-administration values. Urinary NAG activity was improved after this treatment in the microalbuminuric stage of diabetic nephropathy. Furthermore, impairment of renal function was not observed at that stage. It appears that administration of dilazep dihydrochloride from the early stage of diabetic nephropathy may be useful for the improvement of albuminuria and prevention of renal dysfunction.