Urea-Functionalized Heterocycles: Structure, Hydrogen Bonding and Applications.

Ureido-heterocycles exhibiting different triple- and quadruple H-bonding patterns are useful building blocks in the construction of supramolecular polymers, self-healing materials, stimuli-responsive devices, catalysts and sensors. The heterocyclic group may provide hydrogen bond donor/acceptor sites to supplement those in the urea core, and they can also bind metals and can be modified by pH, redox reactions or irradiation. In the present review, the main structural features of these derivatives are discussed, including the effect of tautomerization and conformational isomerism on self-assembly and complex formation. Some examples of their use as building blocks in different molecular architectures and supramolecular polymers, with special emphasis on biomedical applications, are presented. The role of the heterocyclic functionality in catalytic and sensory applications is also outlined.

Systemic non-amyloidotic fibril deposition disease: a probable variant form of fibrillary glomerulonephritis.

Fibrillary glomerulonephritis (FGN) is characterized by deposition of non-amyloidotic fibrillary material in glomeruli, and most patients with the disease show heavy proteinuria and hematuria, and progress into end-stage renal failure. We report a 62-year-old woman with FGN who showed mild proteinuria without hematuria and developed rapidly progressive renal failure requiring hemodialysis. Renal biopsy showed severe tubulointerstitial injury associated with non-amyloidotic fibrillary deposits in the tubular basement membrane, interstitium and vessel walls, in addition to glomeruli. The patient died from liver abscess 1 year after the introduction of hemodialysis. Postmortem examination showed the presence of non-amyloidotic fibrillary deposits arranged in tightly packed electron-dense and bundle-shaped structures in many organs. These findings suggest systemic non-amyloidotic fibril deposition in FGN.

Classic polyarteritis nodosa presenting with rapidly progressive renal insufficiency.

Rapidly progressive renal insufficiency is rare in patients with classic polyarteritis nodosa (cPAN). We describe two cases of cPAN who presented with rapid and progressive deterioration of renal function. Renal biopsies showed severe necrotizing vasculitis in medium-sized arteries but no changes in glomeruli. Combination therapy of corticosteroid and cyclophosphamide resulted in marked improvement of clinical symptoms, amelioration of renal function and lack of subsequent relapse of vasculitis. These findings suggest good prognosis of patients with cPAN who show rapid and progressive deterioration of renal function who respond to immunosuppressive therapy.

Clinical remission and histopathological resolution of nodular lesions in a patient with gamma3 heavy-chain deposition disease.

Heavy-chain deposition disease (HCDD) is a rare entity accompanying to nonamyloidotic monoclonal immunoglobulin deposition disease. We report a case of gamma3-HCDD in which follow-up biopsy could be done after complete remission was achieved by chemotherapy. Follow-up biopsy 2 years after initial biopsy showed remarkable diminution of both nodular glomerular lesions and IgG heavy-chain deposits. This is the first case report to indicate that the original structure of glomeruli in patients with HCDD could be restored within a few years by an appropriate treatment at an early stage of the disease.

Development of an in vitro immunobiotic evaluation system against rotavirus infection in bovine intestinal epitheliocytes.

The bovine intestinal epithelial cell line (BIE cells) expresses the Toll-like receptor (TLR)3 and is able to mount an antiviral immune response after the stimulation with poly(I:C). In the present study, we aimed to further characterise the antiviral defence mechanisms in BIE cells by evaluating the innate immune response triggered by rotavirus (RV) infection. In addition, we attempted to determine whether immunobiotic bifidobacteria are able to confer protection of BIE cells against RV infection by beneficially modulating the antiviral immune response. RV OSU (porcine) and UK (bovine) effectively infected BIE cells, while a significant lower capacity to infect BIE cells was observed for human (Wa) and murine (EW) RV. We observed that viral infection in BIE cells triggered TLR3/RIG-I-mediated immune responses with activation of IRF3 and TRAF3, induction of interferon beta (IFN-ß) and up-regulation of inflammatory cytokines. Our results also demonstrated that preventive treatments with Bifidobacterium infantis MCC12 or Bifidobacterium breve MCC1274 significantly reduced RV titres in infected BIE cells and differentially modulated the innate immune response. Of note, both strains significantly improved the production of the antiviral factor IFN-ß in RV-infected BIE cells. In conclusion, this work provides comprehensive information on the antiviral immune response of BIE cells against RV, that can be further studied for the development of strategies aimed to improve antiviral defences in bovine intestinal epithelial cells. Our results also demonstrate that BIE cells could be used as a newly immunobiotic evaluation system against RV infection for application in the bovine host.

Left ventricular systolic and diastolic function assessed with two-dimensional and doppler echocardiography in "white coat" hypertension.

OBJECTIVES: The aim of this study was to investigate left ventricular function in subjects with "white coat" hypertension, defined as office arterial diastolic pressure > or = 90 and ambulatory daytime pressures < 140/90 mm Hg. BACKGROUND: The white coat arterial pressure response may, by influencing left ventricular function, have a confounding effect in studies of heart disease. METHODS: Two-dimensional and Doppler echocardiography combined with the calibrated subclavian arterial pulse tracing, were used to assess variables of left ventricular function in 26 subjects with white coat hypertension (office arterial diastolic pressure > or = 90 and < 115 mm Hg and ambulatory daytime diastolic pressure > or = 90 mm Hg) and 32 normotensive subjects. RESULTS: In subjects with white coat hypertension, systolic arterial pressure during the echocardiographic examination was significantly higher than ambulatory daytime systolic pressure. This pressure response was positively related to the ratio of the systolic to diastolic pulmonary venous flow peak velocities and to the peak velocity of flow reversion during atrial systole; it was inversely related to the ratio of early to late mitral flow peak velocities. Left ventricular stroke volume, ejection fraction and velocity of circumferential fiber shortening did not differ in the study groups, but left ventricular external work and end-systolic wall stress were increased in the white coat group. CONCLUSIONS: The arterial pressure response in subjects with white coat hypertension is associated with increased left ventricular external work, increased end-systolic wall stress and alterations of left ventricular filling but normal ejection fraction and velocity of circumferential fiber shortening.

Tranilast: a novel weapon against insulin resistance.

Oxidative stress and inflammatory cytokines such as monocyte chemoattractant protein 1 (MCP-1), TGF-beta, and IL-2 are supposed to play crucial roles in the pathogenesis of insulin resistance (IR). Tranilast is an anti-allergic drug which exerts anti-inflammatory and anti-angiogenesis effects through inhibition of expression of MCP-1, TGF-beta, and antigen-induced IL-2 lymphocyte responsiveness. It also possesses a certain antioxidant activity. Considering the above facts and in view of its safety, tranilast may prove invaluable in the treatment of IR.

Analysis of leukocyte surface antigens on ethanol-fixed paraffin-embedded tissue material.

Ethanol-fixed paraffin-embedded specimens of human tissues were studied whether the surface antigens of leukocytes in these tissues can be stained and analyzed. Three-layer indirect immunoperoxidase staining was performed on the ethanol-fixed paraffin-embedded sections by the use of several monoclonal antibodies for whole human leukocytes (Dako LC), B cells (Dako CD-22, 4KB5, and L26; Leu 14), T cells and their subsets (Dako UCHL-1, T1, T3, T4 and T8; Leu 4, 3a and 2a) and monocyte/macrophage lineage (Dako macrophage, Leu M1, M3 and M5). The results were compared with those on fresh-frozen sections. No essential differences were obtained between the paraffin-embedded and the fresh frozen sections stained by the following antibodies; Dako LC for whole human leukocytes; Dako UCHL-1, T3 and Leu 4 for T cells; Dako CD22, 4KB5, L26 and Leu 14 for B cells; Dako macrophage, Leu M1 and M5 for monocyte/macrophage lineage. On the other hand, the subsets of T cells could only be detected on the fresh-frozen sections. The results of the leukocyte analysis on the paraffin-embedded specimens of several renal diseases were very similar to those reported by other investigators on fresh-frozen sections or PLP-fixed materials. Thus, by the use of appropriate monoclonal antibodies, the ethanol-fixed paraffin-embedded material can be used for leukocyte analysis except for the definition of T cell subsets.

Familial lobular glomerulopathy: first case report in Asia.

A 23-year-old male Japanese student presented a unique lobular glomerulopathy characterized by mesangial and subendothelial expansion with numerous periodic acid-Schiff-positive deposits. Electron microscopy showed massive fine granular deposits with a homogeneous distribution. Fibrillar or microtubular structures were not demonstrated. Fibronectin was positive on immunostaining, as was immunoglobulin G and fibrinogen. Familial study revealed that the patient's grandfather, two aunts, and one cousin on his father's side had developed end-stage renal failure. Clinicopathologic features of this patient are identical with those of familial lobular glomerulopathy, which has been previously described by several investigators. Seven of the previously reported families were white and resided in the United States or in European countries. This is the first report of an Asian case, and indicates that this disease universally occurs independently of racial specificity.

Successful treatment with steroid pulse therapy in a case of immunotactoid glomerulopathy with hypocomplementemia.

We report a case of immunotactoid glomerulopathy with severe hypocomplementemia. The patient was a 47-year-old woman who presented with pitting edema, proteinuria, and hypertension. Serological testings were negative or within normal limits except for hypocomplementemia. There were no findings of hematopoietic diseases, cryoglobulinemia, and systemic lupus erythematosus. The renal biopsy specimen showed membranoproliferative glomerulonephritis with numerous periodic acid-Schiff (PAS)-positive deposits. Under electron microscopy, however, microtubular structure was shown in the mesangial matrix and the subendothelial and subepithelial spaces of the peripheral capillary loops. These histological features were compatible with those of immunotactoid glomerulopathy. Although conventional oral steroid therapy failed to have an effect on proteinuria and hypocomplementemia over 3 months, steroid pulse therapy brought dramatic relief: complete remission of proteinuria and normalization of hypocomplementemia. These findings suggest that intensive immunosuppressive therapy may cure a kind of immunotactoid glomerulopathy with hypocomplementemia.

Hemodynamics in white coat hypertension compared to ambulatory hypertension and normotension.

Hemodynamic alterations associated with the blood pressure response in subjects with white coat hypertension may provide insight into the pathophysiologic mechanisms of this condition. Systemic arterial hemodynamics were investigated with a recently validated method based on noninvasive estimates of aortic root pressure and flow in 28 subjects with white coat hypertension (diastolic pressure > or = 90 mm Hg measured by the general practitioner [GP arterial pressure] and ambulatory daytime pressures < 140/90 mm Hg), in 23 subjects with previously untreated, ambulatory hypertension (GP diastolic pressure > or = 90 and < 115 mm Hg and ambulatory daytime diastolic pressure > or = 90 mm Hg), and in 32 normotensive subjects. The groups did not differ significantly concerning age, gender, body surface area, heart rate, stroke index and cardiac index, but total peripheral resistance index was increased and total arterial compliance reduced in the white coat group and the hypertensive group compared to the normotensive group. The subjects in the white coat group with a systolic arterial pressure during echocardiography that was > 5 mm Hg higher than the ambulatory daytime systolic pressure (n = 19) had increased cardiac index, increased total peripheral resistance, and decreased total arterial compliance compared to the normotensive group. The subjects in this group with a hemodynamic pattern characterized by a high ratio of cardiac index/peripheral vascular resistance were significantly younger than the subjects with the opposite pattern. Thus, the blood pressure increase in subjects with white coat hypertension is associated with increased cardiac output, increased peripheral vascular resistance, and reduced total arterial compliance, but the hemodynamic pattern may be influenced by age.

Clinicopathological characteristics of interstitial foam cells in membranous nephropathy.

BACKGROUND: Interstitial foam cells are occasionally observed in various renal diseases, and they have been reported to belong to the monocyte/macrophage (M phi) lineage and to be associated with heavy proteinuria and hyperlipidemia. We investigated the characteristics of interstitial foam cells and their association with proteinuria and hyperlipidemia in idiopathic membranous nephropathy (MN). METHODS: Patients with MN (N = 320) were divided into two groups: group I consisted of 51 patients with interstitial foam cells, and group II consisted of the other 269 without foam cells. We compared clinical parameters and the findings of an immunohistochemical study using monoclonal antibodies to various types of leukocytes and adhesion molecules. RESULTS: The age at renal biopsy, the degree of proteinuria, serum levels of lipids, and other clinical parameters except for sex ratio were not different between the two groups. The ratio of nephrotic patients was compatible between groups I (56.9%) and II (52.8%). All interstitial foam cells were positive for CD68 and 25F9, which are markers for M phi and mature M phi, respectively, but were negative for CD3 or cytokeratin. Interstitial infiltrating cells were positive for CD68 and CD3 but were negative for 25F9. Furthermore, most of interstitial foam cells were positive for both leukocyte function associated antigen-1 (LFA-1) and intercellular adhesion molecule-1 (ICAM-1), but not for ICAM-3 (the third ligand for LFA-1). By contrast, most of infiltrating nonfoamy M phi s were positive for ICAM-3 and LFA-1, however, ICAM-1 was observed on only some of them. CONCLUSION: These results suggest that interstitial foam cells in MN may not depend on proteinuria nor hyperlipidemia directly. The accumulation of foam cells, which have characteristics of mature M phi, may be related to ICAM-1 as a ligand of LFA-1, whereas infiltration of nonfoamy M phi s has a close relationship with ICAM-3. Thus, the formation of interstitial foam cells may be related to the phenotypical transformation of M phi s.

Sublingual nitroglycerin delays arterial wave reflections despite increased aortic "stiffness" in patients with hypertension: a Doppler echocardiography study.

Venodilatation with consequent reduction in left ventricular filling and end-diastolic wall stress is an important mechanism for the beneficial effects of nitroglycerin in ischemic heart disease and in left ventricular failure. The effects of sublingual nitroglycerin on arterial pulsatile hemodynamics are less well defined. Doppler echocardiography and the calibrated subclavian artery pulse tracing were used to assess hemodynamics in subjects with sustained arterial hypertension (n = 25) before and 5 to 10 minutes after sublingual deposition of 0.5 mg glyceryl trinitrate. Aortic characteristic impedance was calculated by averaging the modulus of the input impedance (ratio of pressure to flow) at high frequencies and by calculating the ratio of pressure and flow increments during upstroke. The pressure wave was split into forward and backward components, and the reflection coefficient (the ratio of backward to forward pressures) was calculated. Parameters of the arterial bed were estimated by using 2- and 3-element Windkessel models. Nitroglycerin delayed the return of arterial wave reflections by 17% (P =.02) and increased aortic characteristic impedance by 20% (P =. 01), but it did not influence total arterial compliance. Mean arterial pressure decreased 7% (P =.0001), but pulse pressure did not change. Stroke volume and the acceleration time of aortic root flow decreased by 13% (P =.0001) and 8% (P =.01), respectively. Cardiac output decreased 7% (P =.01), despite an increase in heart rate of 10% (P =.0001). Peripheral resistance tended to decrease (4%, P =.06). Thus, in subjects with sustained hypertension, sublingual nitroglycerin dilates peripheral, predominantly muscular arteries with a subsequent delayed return of reflected pressure waves. Reflex activation of the sympathetic nervous system with consequent increased acceleration of left ventricular ejection seems to counteract the effect of reduced mean arterial pressure (distending pressure) with respect to the "stiffness" of the aorta.

Membranoproliferative glomerulonephritis induced by portosystemic shunt surgery for non-cirrhotic portal hypertension.

The liver and spleen both have important phagocytic functions and contain monocytes/macrophages which clear immune complexes. We describe here three patients who presented proteinuria and hematuria 7 to 13 years after portosystemic shunt surgery, which diverted portal venous blood to the systemic circulation. They had hematemesis and/or melena and underwent mesocaval shunt surgery and splenectomy in childhood because of non-cirrhotic portal hypertension with esophageal varices. Renal biopsy specimens revealed findings characteristic of membranoproliferative glomerulonephritis (MPGN) type I. Immunohistologically, these three cases were accompanied by a distinct IgA deposition along with a marked C3 deposition. The IgA observed in these three cases contained not only IgA1 but also IgA2, which is the predominant form of mucosal IgA. On the other hand, of 20 patients with idiopathic MPGN type I with IgA deposition (n = 20), only two were positive for IgA2, and the distribution was focal and segmental. Our study shows that MPGN type I may have developed secondary to portosystemic shunt. This secondary form of MPGN type I may be caused by a reduced clearance of immune complexes in the liver and their deposition in the glomerulus, since a portosystemic shunt routes portal venous blood from the intestinal tract directly to the systemic circulation.

[A case report of angina pectoris associated with hypereosinophilia in a patient on continuous ambulatory peritoneal dialysis (CAPD)].

We report a case of hypereosinophilia which was associated with the onset of anginal attacks. A 64-year-old man progressed to end-stage renal failure due to diabetic nephropathy, and was treated with continuous ambulatory peritoneal dialysis (CAPD). He had no past history of angina pectoris nor hypereosinophilia. Three weeks after the initiation of CAPD, the eosinophil count in peripheral blood increased (up to 4093/mm3). Two weeks later, he suffered from an anterior chest pain attack, and angina pectoris was diagnosed. As a result of treatment with isosorbide dinitrate and prednisolone, hypereosinophilia disappeared rapidly and repeated episodes of anginal attacks also disappeared. After an interval of 3 months, however, hypereosinophilia (up to 15190/mm3) and anginal attacks recurred. He underwent coronary angiography, in which no stenotic change was observed. The administration of prednisolone was effective in the treatment of these episodes. Although a close relationship between hypereosinophilia and anginal attack has been reported, it has not been known in CAPD patients as described here. Attention should be paid to these relationships in CAPD patients, because hypereosinophilia is frequently observed in maintenance peritoneal dialysis patients.

[Two aged patients with chronic renal failure and chronic disseminated intravascular coagulation secondary to aortic aneurysms: effect of continuous subcutaneous heparin infusion therapy].

We describe here two cases of chronic disseminated intravascular coagulation(DIC) secondary to aortic aneurysms. The patients were 78- and 84-year-old males, who visited our hospital to receive hemodialysis therapy for chronic renal failure probably due to nephrosclerosis. They had mild bleeding tendency and thrombocytopenia(< 10 x 10(4)/microliter). Coagulation test revealed the findings of chronic DIC in both patients, and computed tomography showed abdominal and thoracoabdominal aortic aneurysms with mural thrombi, respectively. In one patient, subcutaneous hemorrhage after vascular access surgery had continued for a month. However, the hemorrhage and swelling of the limb disappeared after continuous subcutaneous heparin infusion(CSHI) therapy in a daily dose of 10,000-14,000 unit. These findings suggest that chronic DIC secondary to aortic aneurysm should be considered when bleeding tendency and thrombocytopenia are observed in aged patients, and that CSHI is the choice of therapy for the bleeding tendency of chronic DIC.

[Minimal change nephrotic syndrome with predominant mesangial IgA deposits: clinicopathological study].

It has been reported that minimal change nephrotic syndrome (MCNS) shows no deposit of immunoglobulins or complement components in the glomeruli. We found 6 patients with IgA deposits in the glomeruli among 101 patients with MCNS, and examined the clinicopathological features of these cases. In all cases, light microscopy showed minor glomerular abnormalities. However, immunohistochemical study demonstrated marked IgA deposits in the glomerular mesangium. IgM was detected in 5 cases, IgG in 2, C3 in 2, and Clq in 1. On electron microscopy, small mesangial deposits were found in all cases and foot process effacement was partially demonstrated. There were no abnormalities in the glomerular basement membrane. The renal functions were within normal ranges in all 6 cases. In three cases, biopsies were performed within a month after the initiation of profuse proteinuria. In the other three cases, frequent relapses had been observed for 6 to 15 years before the biopsies. However, all patients ultimately revealed complete remission with corticosteroid treatment. Serum IgA levels were within normal range in examined 4 cases. Hematuria was negative in all of them. The clinical findings seem to be identical to MCNS rather than IgA nephropathy, and IgA deposits may have no pathogenetic significance, although the pattern of deposition looks quite similar to that of IgA nephropathy. These results indicate that the renal lesions in the 6 patients may belong to the subtype of MCNS, rather than IgA nephropathy.

[Analysis of intraglomerular and interstitial infiltration of leukocytes in membranous nephropathy with focal segmental glomerulosclerosis].

We investigated infiltrating cells in the glomeruli and interstitium in biopsy specimens from 41 cases with membranous nephropathy (MN) and found that 21 had focal segmental glomerulosclerosis (FGS) and 20 did not. There was no significant difference between groups MN +FGS and MN regarding age, interval from onset, serum creatinine level and urine protein excretion when the biopsy was performed. The cells were analyzed with 3-layer indirect immunoperoxidase techniques using monoclonal antibodies to leukocyte common antigen, T cells, B cells and monocytes/macrophages (Mo/M phi). The numbers of leukocytes in both glomeruli and interstitium increased significantly in group MN+FGS as compared to those in group MN, respectively. Most of the leukocytes infiltrating the glomeruli were Mo/M phi, while T cells and Mo/M phi were predominant in the interstitium. There was a significant correlation between the numbers of intraglomerular and interstitial Mo/M phi in group MN+FGS, but not in group MN. Follow-up periods after the biopsy were not significantly different between the groups. At the final points of follow-up, urine protein excretion significantly decreased in group MN, but not in group MN+FGS. In group MN+FGS, serum creatinine levels were twice the level found at the biopsy in 5 cases, and 2 required hemodialysis therapy. Renal functions were not deteriorated in any cases of group MN. These findings suggest that FGS may be one the deleterious factors in MN, which may facilitate the infiltration of Mo/M phi in both glomeruli and interstitium and T cells in the interstitium.

[A case of hepatitis C virus associated membranous glomerulonephritis ameliorated by corticosteroid therapy].

We report a 50-year-old male patient with hepatitis C virus (HCV)-associated membranous glomerulonephritis (MN), for which he had been treated with corticosteroid therapy for one and a half years. This patient received blood infusion at 38 years of age. He visited our hospital because of liver dysfunction at 42 years. One year later, proteinuria and microhematuria were pointed out (43 years). Renal biopsy revealed MN with focal fibrocellular crescents. HBsAg, cryoglobulin, rheumatoid factor were all negative. Prednisolone was administered at the dose of 30 mg/day for 4 weeks and tapered subsequently. The steroid treatment was effective (urinary protein excretion: 4.2-->0.3 g/day, serum albumin: 2.4-->4.0 g/dl, 3 months later), and transaminase slightly elevated (GPT 50-->60-80 IU/l). One and a half years later he proved to be positive for HCV antibody, and corticosteroid administration was terminated. Subsequently proteinuria increased, and reached 3.0 g/day 6 years later. However, serological markers and ultrasonographic study for chronic hepatitis revealed mild changes of the liver. These findings suggest that corticosteroid therapy is not contraindicated against HCV-associated MN, and may possibly be used as the treatment for this condition.

[A case of IgA nephropathy with numerous interstitial foam cells--analysis of infiltrating mononuclear leucocytes in renal tissue].

A 27-year-old female was admitted to our hospital in order to examine proteinuria and microscopic hematuria. Light microscopic findings of her kidney showed proliferation of mesangial cells and numerous interstitial foam cells. Immunofluorescent and electron microscopic findings revealed IgA nephropathy. Immunoperoxidase studies using monoclonal antibodies disclosed that interstitial foam cells were positive for antibodies of the monocyte/macrophage lineage and also expressed adhesion molecules (CD11a, b, c, LFA-1) and MHC-class II antigens. Hereditary nephritis as Alport syndrome was negated by her familial history and electron microscopic study. We considered that it was a rare and interesting case with numerous interstitial foam cells, because the patient did not have hyperlipidemia as in nephrotic syndrome.