Imbalance of interleukin-18 and interleukin-18 binding protein in patients with IgA nephropathy implicating renal vasculopathy.

BACKGROUND: Interleukin-18 (IL-18) is a proinflammatory cytokine which induces interferon-γ production and plays a crucial role in immune systems. IL-18 binding protein (IL-18BP) is a naturally occurring inhibitor of IL-18. The aim was to investigate the involvement of IL-18 and IL-18BP in IgA nephropathy (IgAN). METHODS: Serum samples from 21 IgAN patients and 16 idiopathic membranous nephropathy (MN) patients and 32 healthy controls were assayed by an enzyme-linked immunosorbent method. RESULTS: Compared to the controls, IgAN patients showed significantly higher levels of IL-18 and the increased IL-18/IL-18BP ratio. Despite IL-18 elevation, the levels of IL-18BP did not parallel the increase of IL-18, which resulted in an increased IL-18/IL-18BP ratio. Furthermore, the ratio in patients with renal vasculopathy was significantly increased compared to those without arteriolar lesions. CONCLUSIONS: These findings provide the first evidence that there is an imbalance of IL-18/IL-18BP ratio in IgAN patients, which may be associated with the pathophysiology of renal vasculopathy.

Pneumocystis carinii Infection in a domestic goat (Capra hircus domesticus) with multibacillary paratuberculosis.

Pneumocystis carinii (P. carinii) is an opportunistic fungal pathogen commonly found in many mammalian host species, but rarely in goats. A 3-year-old, female, Tokara-native-goat (Capra hircus domesticus) died of apparent malnutrition caused by multibacillary paratuberculosis. While inflammatory response was slightly observed in the respiratory organs, P. carinii trophozoites and cysts were immunohistochemically observed in the pulmonary alveoli of the infected animal. P. carinii specific DNA was amplified from the formalin fixed and paraffin embedded lung samples. Molecular phylogenetic analyses of the mitochondrial large subunit ribosomal RNA region of P. carinii revealed genetic divergence from previously described P. carinii isolates from other mammalian host species. This is the first description of concurrent infection with P. carinii and the Mycobacterium avium subspecies paratuberculosis in a domestic goat.

Effects of cyclosporine on bone mineral density in patients with glucocorticoid-dependent nephrotic syndrome in remission.

PURPOSE: Cyclosporine (CsA) is often prescribed to patients with glucocorticoid (GC)-dependent nephrotic syndrome. Although it is well known that long-term administration of GC causes osteoporosis, the effects of CsA on bone metabolism are not fully established. Therefore, we examined the effects of CsA on bone metabolism in patients with GC-dependent nephrotic syndrome in remission. METHODS: We followed 23 patients treated with prednisolone alone (GC alone group) and 17 patients treated with CsA in combination with prednisolone (GC + CsA group). Bone mineral density (BMD) was measured by dual-energy X-ray absorptiometry, and biochemical markers of bone metabolism were simultaneously measured in serum and urine samples. RESULTS: BMD decreased significantly in the GC group from 752 to 623 mg/cm(2) but non-significantly in the GC + CsA group from 751 to 684 mg/cm(2). Although the cumulative dose of GC increased in both groups, there were no significant differences in biochemical markers at either the start or the end of the study. Vertebrate bone fracture and other side effects associated with CsA treatment did not occur in our study. CONCLUSIONS: Our results indicate that CsA does not accelerate GC-induced osteoporosis in patients with nephrotic syndrome. We conclude that CsA is appropriate for the treatment of GC-dependent nephrotic syndrome, because it does not adversely affect bone metabolism and has favorable glomerular effects.

High circulating levels of interleukin-18 binding protein indicate the severity of glomerular involvement in systemic lupus erythematosus.

In systemic lupus erythematosus (SLE), glomerular involvement often progresses with the activity of the disease. Immune complexes and abnormal secretion of cytokines are thought to be involved in the central mechanism of the development of lupus nephritis. We investigated serum levels of interleukin 18 (IL-18), a proinflammatory cytokine, and its natural antagonist IL-18 binding protein (IL-18 BP) in 45 patients with lupus nephritis. IL-18 levels were significantly increased in patients with Class II, Class III, and Class IV lupus nephritis compared with the level in a healthy control group. However, the levels stayed within the non-significant range in Class V. IL-18 BP levels were significantly increased in patients with Class III and Class IV lupus nephritis, in which histological activity and chronicity are severe. However, IL-18 BP levels stayed within the non-significant range in Class II and Class V, in which histological markers are mild. We also compared the levels of IL-18 and IL-18 BP in patients with and without glomerular infiltration of inflammatory cells. IL-18 was increased regardless of glomerular infiltration. However, IL-18 BP was increased only in patients with glomerular infiltration. These data suggest that IL-18 levels indicate the extent of the offending inflammatory response not only in the bloodstream but also in renal tissue, and that high IL-18 BP levels indicate the severity of existing glomerular injury.

Interleukin-18 contributes more closely to the progression of diabetic nephropathy than other diabetic complications.

Diabetic complication is comprised of a wide variety of pathophysiological factors involving proinflammatory cytokines, adipokines, and oxidative stress, among others. Each of these complications differs in their incidence and the stage of their occurrence. We examined cytokines and stress markers in 48 patients with type 2 diabetes mellitus and compared the difference of their contribution to pathogenesis between nephropathy and other diabetic complications. Hemoglobin A1c correlated with the level of low-density lipoprotein-cholesterol, and significantly elevated in the severe macroangiopathy group. Cystatin C increased in the severe microangiopathy groups but did not increase in the macroangiopathy group. The levels of interleukin 18 (IL-18), high-sensitive CRP (H-CRP), liver-type fatty acid binding protein, and 8-hydroxy-2-deoxyguanosine increased in the severe microangiopathy group. These data suggest the participation of proinflammatory signaling and oxidative stress in the progression of microangiopathy. In particular, IL-18 and H-CRP were significantly elevated only in the severe nephropathy group but did not significantly elevate in other complications. These data suggest another effect of IL-18 on glomerulus in addition to its proinflammatory effect. In conclusion, we propose that IL18 has a specific role that contributes more closely to the progression of diabetic nephropathy than other diabetic complications.

Serum interleukin-18 binding protein increases with behavior different from IL-18 in patients with diabetic nephropathy.

We investigated alterations between serum interleukin 18 (IL-18) and IL-18 binding protein (18BP) in T2DM patients. 18 BP began to increase after IL-18 increased and reached a threshold, in which case kidney dysfunction would have developed. These data indicate that 18BP might express glomerular dysfunction more closely than IL-18.

[Longstanding intractable massive ascites caused by chronic lupus peritonitis with nephrotic syndrome: a case report].

A 36-year-old woman with systemic lupus erythematosus (SLE) and nephrotic syndrome showed massive ascites. She was admitted to our hospital because of edema in both legs and a remarkably distended non-tender abdomen. On admission, massive ascites was observed in the abdominal CT scan findings. Laboratory examination of the ascites showed low levels of total protein (1.5 g/dL), albumin (0.5 g/dL) and LDH (89 IU/L), which were characterized as ascites per diapedesis. In addition, she was diagnosed with SLE and nephrotic syndrome from the clinical and laboratory findings. We treated her with steroid therapy, including methylprednisolone plus therapy. Although the serological abnormalities with SLE had normalized and urinary protein almost disappeared on the 51th hospital day, the ascites had not improved at all. These findings indicated that she had suffered from chronic lupus peritonitis, complicated with nephrotic syndrome and we had continued to treat her with prednisolone for a long time. The ascites was remarkably diminished at 220 days after admission. We believe that in addition to nephrotic syndrome, impaired vascular circulation caused by chronic lupus peritonitis might have contributed to accumulation of the massive ascites.

Characterization of glutamate decarboxylase mediating gamma-amino butyric acid increase in the early germination stage of soybean (Glycine max [L.] Merr).

Glutamate decarboxylase (GAD) is an enzyme that catalyzes the production of gamma-amino butyric acid (GABA) from glutamate through a decarboxylation reaction. A full-length cDNA encoding glutamate decarboxylase (GmGAD1) was isolated from germinating soybean seeds (Glycine max [L.] Merr.). The GmGAD1 gene had a 1512-bp open reading frame, which encodes 503 amino acids. According to its sequence similarity with other GAD genes, GmGAD1 was classified into GAD1 in the plant GAD family. Recombinant GmGAD1 protein expressed in E. coli catalyzed alpha-decarboxylation of glutamic acid. The levels of GABA were rapidly increased in soybean seeds during the early imbibition period (6 h) of germination or during the soaking treatment, whereas mRNA of GmGAD1 gene was not detected in these materials. The GmGAD1 protein was observed in seeds of various states such as developing, matured and soaking. These data suggest that the increased levels of GABA during the early stage of germination or soaking treatment were mediated by GmGAD1 protein synthesized in developing soybean seeds.

[Educative effect of feedback after medical interview in objective structured clinical examination].

OBJECTIVE: Objective Structured Clinical Examination (OSCE) is widely used to assess the core competency of dental residents. However, the educative effect of feedback in OSCE has not been fully examined. Therefore, we investigated the educative effect of formative feedback in a medical interview station. METHODS: The subjects were 51 residents in the clinical training course of our dental hospital. After completing the medical interview station, residents were individually given formative feedback by evaluators and standardized patients. Two months later, residents were asked to fill in a questionnaire about the contents of feedback and self-rating mental strain level during OSCE. Videotaped performance and feedback were reviewed by investigators to check the answers to the questionnaire. RESULTS: Evaluators provided an average of 3.1 feedback items, and standardized patients provided an average of 1.6 feedback items for each resident. However, each resident remembered an average of 1.3 feedback items from evaluators and 0.9 from standardized patients. The lower the score of residents in the medical interview station, the more feedback items were given to residents. A significant negative correlation was found between the score of evaluators and self-rating mental strain level (Spearman rho = -0.326, p = 0.019). CONCLUSION: For effective feedback, evaluators or standardized patients should focus on 2 to 3 items of essential points in OSCE. Repetition of feedback using videotaped performance may be useful to improve communication skills for medical interview.

The influence of lifestyle modification on carotid artery intima-media thickness in a suburban Japanese population.

To evaluate the influence of lifestyle modification with and without lipid-lowering drug therapy on the carotid arterial wall, we did a 2 year prospective ultrasound study of carotid intima-media thickness (IMT) in 1390 male and female residents of a suburban Japanese town. According to total cholesterol (TC) level at baseline, subjects were classified into a lifestyle modification alone group (TC >/= 220 mg/dl, n = 437), a lifestyle modification with lipid-lowering drug group (TC >/= 220 mg/dl, n = 159), and a control group (TC < 220 mg/dl, n = 794). After 2 years of follow-up, both sexes of both treatment groups showed significant reductions of TC, low-density lipoprotein cholesterol (LDL-C), and IMT, although TC continued over 220 mg/dl in some subjects in the lifestyle modification group. The reduction of TC and LDL-C was significantly higher in the lifestyle modification with lipid-lowering drug group than in the lifestyle modification alone group. Although the IMT reduction was not statistically different between the treatment groups of either sex, the reduction of IMT was greater in the lifestyle modification with lipid-lowering drug group than in the lifestyle modification alone group. Our results indicate that comprehensive lifestyle modification can reduce carotid IMT in the general population, with or without the use of lipid-lowering drugs and that cholesterol reduction is of benefit even when TC level remain above the recommended level.

Association of Chlamydia pneumoniae antibody with the cholesterol-lowering effect of statins.

To investigate the association between Chlamydia pneumoniae (C. pneumoniae) infection and atherosclerosis, we compared the effect of lipid-lowering drugs on carotid intima-media thickness (IMT) between patients who were positive and negative for C. pneumoniae antibodies. A total of 165 asymptomatic hypercholesterolemic patients were randomized to probucol (500 mg per day, n = 82) or pravastatin (10 mg per day, n = 83) and followed for 2 years. The 2-year change of IMT in the common carotid artery was the primary endpoint, while mean IMT change and major cardiovascular events were secondary endpoints. C. pneumoniae antibodies (IgA and IgG) were measured by enzyme-linked immunosorbent assay. The 50 patients without C. pneumoniae antibodies showed significant reduction of IMT progression (-19%), while no significant change of IMT was noted in the 115 antibody-positive patients (-6%). Significant inverse associations were found between the reduction of IMT progression and the C. pneumoniae IgA- and IgG-antibody index (P < 0.01 and 0.01, respectively). No significant differences in the reduction of serum total-cholesterol and LDL-cholesterol were found between antibody-positive and -negative patients. There was no significant difference of efficacy between probucol and pravastatin. These observations suggest that C. pneumoniae infection reduces the effect of lipid-lowering therapy on carotid atherosclerosis and that this organism may play a role in the progression of atherosclerosis.

[Home care workers' oral health awareness and practice for disabled elderly].

The purpose of this study was to investigate the level of oral health awareness, and to explore the needs for home care workers to provide oral health care for disabled elderly. We conducted a questionnaire survey at two home-help service centers and a social welfare council. Subjects for this investigation were 63 home care workers. The results were as follows: 1. Ninety-six percent of home care workers thought it was necessary to provide oral health care for disabled elderly, but only 11 percent of them put oral care into practice on a daily basis. 2. From the results of a cause and effect diagram, necessities of oral care were summarized as six major causes: 1) Disabled elderly are often unable to brush their teeth, 2) The oral hygiene level may affect physical condition, 3) Disabled elderly should be protected from oral diseases, 4) Disabled elderly should have their mouths kept clean, 5) Eating and swallowing may become increasingly difficult, 6) Disabled elderly should take in adequate nutrition. 3. Sixty-eight percent of home care workers took part in a training course of nursing care including oral care. 4. Home care workers, dentists, dental hygienists, and nurses taught oral health care to home care workers. 5. From the results of a cause and effect diagram, there were three major items that home care workers want to know: 1) denture management, 2) the routine of oral care, 3) infection control. 6. Home care workers recognized that oral care should be provided by family members of disabled elderly or home care workers.

Prevalence of antibody to Chlamydia pneumoniae in residents of Japan, the Solomon Islands, and Nepal.

Sera of 4,050 residents from Japan, 276 from the Solomon Islands, and 602 from Nepal were tested by an enzyme-linked immunosorbent assay to determine the prevalence of antibody to Chlamydia pneumoniae. The prevalence of IgG and IgA antibodies was significantly higher in the Solomon Islands (64.9% and 82.2%) and Nepal (73.1%, and 69.8%) than in Japan (53.6% and 41.1%). These prevalence rates increased throughout the teenage years in the Solomon Islands and Japan and leveled off with age, whereas in Nepal the prevalence rates gradually increased with age. The prevalence of a high (> 3.0) IgA antibody index, which is suggestive of acute infection, was significantly higher in the Solomon Islands (34.8%) than in Japan (3.2%) and Nepal (10.5%). The prevalence of IgG antibody ranged from 46.4% to 67.7%, and the prevalence of IgA antibody ranged from 33.7% to 61.8% in the four difference areas of Japan. These findings indicate considerable differences in the prevalence of antibodies to C. pneumoniae by age in these nations and between the regions of Japan tested.

Chlamydia pneumoniae seropositivity and early carotid atherosclerosis in a suburban Japanese population.

To evaluate the association between Chlamydia pneumoniae (C. pneumoniae) infection and carotid atherosclerosis (CA), we investigated CA assessed by carotid B-mode ultrasound and known or suspected atherosclerotic risk factors including C. pneumoniae IgG and IgA antibodies in 2410 residents (mean age 54.5+/-13.6 years, 697 men) of a suburban Japanese town. CA was found in 30.1% of men and in 14.0% of women, IgG in 59.4% and in 51.4%, and IgA in 36.9% and in 32.4%, respectively. In univariate analysis, most conventional atherosclerotic risk factors and IgA antibody were significantly associated with CA in both sexes, but not IgG. In multivariate logistic regression analysis, independent risk factors for CA were confirmed with age and triglycerides (TG) in men and age, systolic blood pressure, pack-years of smoking, and low-density lipoprotein cholesterol (LDL-C) in women, but not IgG and IgA in either sex. These results do not support C. pneumoniae infection as an important risk factor for CA in this Japanese population.

Effects of probucol and pravastatin on common carotid atherosclerosis in patients with asymptomatic hypercholesterolemia. Fukuoka Atherosclerosis Trial (FAST).

OBJECTIVES: This study investigated the effect of reducing serum lipids on carotid artery intima-media thickness (IMT) in asymptomatic patients with hypercholesterolemia from Fukuoka, Japan. BACKGROUND: Carotid atherosclerosis is a strong, independent predictor of morbidity and mortality in patients with coronary heart disease (CHD). METHODS: A total of 246 asymptomatic hypercholesterolemic patients (mean age 66 years) were randomized to receive either probucol (500 mg/day, n = 82) or pravastatin (10 mg/day, n = 83) or to enter a control group (diet alone, n = 81); they were followed for two years. The change in IMT in the common carotid artery was the primary end point measure, and the incidence of major cardiovascular events was the secondary measure. RESULTS: Over the two-year period, serum low-density lipoprotein (LDL) cholesterol was significantly reduced in the pravastatin group (36%), the probucol group (29%) and the control group (12%) (p < 0.0001, p < 0.0001 and p < 0.05, respectively). After two years, the probucol and pravastatin groups showed a significant reduction in IMT (-13.9% and -13.9% and p < 0.01 and p < 0.01, respectively), but there was significant IMT thickening (23.2%; p < 0.05) in the control group. Probucol reduced the rate of IMT increase, independently of its reduction of LDL or high-density lipoprotein cholesterol. Moreover, there was a significantly lower incidence of cardiac events in the probucol group (2.4%) than in the control group (13.6%) (p = 0.0136). CONCLUSIONS: Probucol reduced cholesterol levels and stabilized plaque, leading to a lower incidence of cardiac events in these hypercholesterolemic patients.