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.

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.

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.

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.

Relationship between function and perfusion early after acute myocardial infarction.

To assess the relationship between baseline left ventricle function, functional reserve and resting myocardial perfusion in patients with acute myocardial infarction (AMI). After AMI the presence of dysfunctioning but viable myocardium plays a determinant role in clinical outcome. Regional ventricular function was evaluated by echocardiography both in resting conditions and during dobutamine infusion (10 microg/kg/min). Perfusion was assessed by magnetic resonance imaging in a single slice approach where the first pass of an intravenously injected bolus of gadolinium-based contrast agent was followed through six regions of interest within the myocardium. In each patient a region with normal function was used as reference and the cross-correlation coefficient (CCC), which described the myocardial perfusion relatively to the reference region (CCC = 1 means equivalent perfusion), was obtained for the other five myocardial regions. Twenty-two patients were enrolled into the study. Sixty-one segments had normal function and normal perfusion (CCC = 0.92+/-0.23). The perfusion deficit was more marked in the 29 regions with resting akinesia-dyskinesia than in the 20 hypokinetic regions (CCC = 0.71+/-0.45 vs. 0.84+/-0.23; p < 0.05). Out of the 29 regions with resting akinesia-dyskinesia the 13 segments which showed functional improvement following dobutamine had a higher resting perfusion than the 16 segments which were unresponsive to dobutamine (CCC = 0.83+/-0.32 vs. 0.61+/-0.52, p < 0.05). Similarly, out of the 20 regions with resting hypokinesia the 11 segments having functional reserve showed an higher resting perfusion than the segments which did not (0.96+/-0.21 vs. 0.69+/-0.19; p < 0.05). Early after AMI, the perfusion deficit reflects the severity of the mechanical dysfunction. In regions with baseline dyssynergy resting perfusion is, in general, higher when contractile reserve can be elicited by stress-echo.

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.

[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.

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.

[White coat hypertension]. / Kontorhypertensjon.

The prevalence of white coat hypertension, which is defined by hypertension in the physician's office, and normotension at other times, may be as high as 30% in a hypertensive population. Since white coat hypertension is associated with a low degree of end-organ damage and, accordingly, a potential favourable prognosis, the use of ambulatory blood pressure recordings has increased with the aim of identifying hypertensive subjects who may not need medical treatment. White coat hypertension is, however, not yet clearly defined, and there seems to be evidence that such subjects may have reduced vasodilator capacity. Low arterial compliance, a feature associated with hypertension in the elderly, seems to be another characteristic. Hence, although the prognostic significance of white coat hypertension has not yet been completely defined, there is accumulating evidence that ambulatory blood pressure recordings may serve as an important tool in the risk assessment of subjects with arterial hypertension.

Total arterial compliance in ambulatory hypertension during selective beta1-adrenergic receptor blockade and angiotensin-converting enzyme inhibition.

Aortic root flow and pressure estimates were obtained noninvasively with Doppler echocardiography and calibrated subclavian artery pulse tracing in 30 subjects with ambulatory hypertension in a randomized, crossover study with 4 weeks' treatment and washout periods. Total arterial compliance, assessed by use of a three-element Windkessel model of the arterial tree, increased 42% with atenolol (50-100 mg once daily), and 7% (p = NS) with captopril (25-50 mg twice daily). Atenolol reduced mean arterial pressure by 15%, heart rate by 22%, and cardiac output by 14%, and increased acceleration time of aortic root flow by 17% and stroke volume and ejection time each by 11%. Captopril reduced mean arterial pressure and total peripheral resistance each by 7%. Acceleration time of aortic root flow, ejection time, heart rate, stroke volume, and cardiac output were not significantly changed by captopril. We conclude that total arterial compliance, at the operational blood pressure, increases during selective beta1-adrenergic receptor blockade in subjects with ambulatory hypertension. Although the main mechanism may be a reduction in mean arterial pressure, it should be considered whether reduced heart rate may play an additional role. The nonsignificant increase in total arterial compliance during angiotensin-converting enzyme inhibition may primarily be a consequence of a modest reduction of the mean arterial pressure.

Influence of body size and left ventricular ejection dynamics on total arterial compliance determined using Doppler echocardiography and subclavian artery pulse tracings in healthy humans.

The aim was to investigate determinants of total arterial compliance in healthy humans. Estimates of aortic root pressures and flow were obtained non-invasively with the calibrated subclavian artery pulse tracing and Doppler echocardiography in 37 males (27-76 years) and 45 females (20-77 years). Total arterial compliance, estimated using a three-element vascular model, correlated positively with body height (r = 0.45, p < 0.01) and acceleration time of aortic root flow (r = 0.32, p < 0.01) and inversely with age (r = -0.34, p < 0.05), heart rate (r = -0.33, p < 0.01), and mean arterial pressure (r = -0.51, p < 0.01). Multivariate analysis indicated that height and heart rate contributed most to the prediction of total arterial compliance. The inclusion of mean arterial pressure within the model significantly reduced the contribution of age, but not that of body height and heart rate. After adjustment for height and heart rate, total arterial compliance did not differ significantly between gender. Thus, total arterial compliance, as assessed in this study, seems to reflect both arterial capacity and viscoelastic properties of the arterial wall. Differences in body size, heart rate and mean arterial pressure should be considered when comparing total arterial compliance in different groups.

Significance of leukocyte infiltration in membranous nephropathy with segmental glomerulosclerosis.

AIM: To clarify the role of leukocyte subsets in the development of glomerulosclerosis (GS) and interstitial lesions which may contribute to the prognosis of membranous nephropathy (MN), we investigated infiltrating cells in both glomeruli and interstitium in biopsy specimens. METHODS: Forty-one cases of MN were divided into two groups: MN with segmental GS (MN+GS; n = 21) and MN without GS (MN-GS; n = 20). There was no significant difference between both groups regarding clinical data at the time of the renal biopsy. The cells were analyzed with a three-layer indirect immunoperoxidase method using monoclonal antibodies against leukocyte common antigen, T cells, B cells, and monocytes/macrophages (Mo/Mstraight phi). RESULTS: Renal function tended to deteriorate during the final follow-up period in group MN+GS, but not in group MN-GS. The number of glomerular and interstitial leukocytes in group MN+GS were significantly higher than those in group MN-GS. Leukocytes were mostly Mo/Mstraight phi in the glomerulus, while T cells and Mo/Mstraight phi were predominant in the interstitium. In group MN+GS, there was a significant correlation in number of Mstraight phi (CD68+) between glomeruli and interstitium, but not in group MN-GS. CONCLUSION: The results suggest that Mo/Mstraight phi may play an important role in the development of segmental GS and interstitial lesions in MN which may be responsible for the incurability and poor prognosis.