Regulatory effects of inducible nitric oxide synthase on cyclooxygenase-2 and heme oxygenase-1 expression in experimental glomerulonephritis.

BACKGROUND: We explored whether inducible nitric oxide synthase (iNOS) driven nitric oxide (NO) production regulates expression of iNOS, endothelial NOS (eNOS), Cyclooxygenase-2 (COX-2), and Hemeoxygenase-1 (HO-1) proteins in a rat model of glomerulonephritis induced by antibody raised in rabbits against rat glomerular basement membrane (anti-GBM). METHODS: Rats were injected either with non-immune serum (control), or anti-GBM serum. In a group of rats N6-(1-iminoethyl)-L-lysine (L-NIL) was administered prior to injection of anti-GBM serum to inhibit iNOS activity. Urinary nitrite plus nitrate (NOx) excretion was assessed to determine the extent of iNOS inhibition by L-NIL. Urinary albumin excretion was assessed to determine extent of proteinuria. Urinary PGE2 was assessed as a marker of COX activity. Glomeruli were harvested 24 h after injection of anti-GBM serum and ED1, COX-2, iNOS, eNOS and HO-1 expression was analysed by Western blot analysis. RESULTS: iNOS activity in glomeruli was effectively reduced in L-NIL-treated nephritic animals. In these animals, there was exacerbation of proteinuria and reduction in urinary PGE2 levels without changes in the extent of macrophage infiltration in glomeruli. In nephritic animals, there was an increase in glomerular protein levels of COX-2, HO-1 and iNOS, but not of eNOS. While L-NIL treatment reduced glomerular HO-1, levels of COX-2 and iNOS increased; but not that of eNOS. CONCLUSIONS: The observations indicate that in glomerulonephritis iNOS-driven NO production acts as a negative feedback regulator of iNOS itself, suppresses COX-2 levels, and maintains HO-1 levels.     

Microstructural abnormalities in MEWDS demonstrated by ultrahigh resolution optical coherence tomography

BACKGROUND: Histopathological studies of acute multiple evanescent white dot syndrome (MEWDS) have not been reported because of the transient and benign nature of the disease. Ultrahigh resolution optical coherence tomography (UHR-OCT), capable of high resolution in vivo imaging, offers a unique opportunity to visualize retinal microstructure in the disease. METHODS: UHR-OCT images of the maculae of five patients with MEWDS were obtained and analyzed. Diagnosis was based on clinical presentation, examination, visual field testing, and angiography. RESULTS: UHR-OCT revealed disturbances in the photoreceptor inner/outer segment junction (IS/OS) in each of the five patients (six eyes) with MEWDS. In addition, thinning of the outer nuclear layer was seen in the case of recurrent MEWDS, suggesting that repeated episodes of MEWDS may result in photoreceptor atrophy. CONCLUSIONS: Subtle disruptions of the photoreceptor IS/OS are demonstrated in all eyes affected by MEWDS. UHR-OCT may be a useful adjunct to diagnosis and monitoring of MEWDS.     

Induction of selected lipid metabolic enzymes and differentiation-linked structural proteins by air exposure in fetal rat skin explants

The epidermal permeability barrier of premature infants matures rapidly following birth. Previous studies suggest that air exposure could contribute to this acceleration, because: (i) development of a structurally and functionally mature barrier accelerates when fetal rat skin explants are incubated at an air-medium interface, and (ii) occlusion with a water-impermeable membrane prevents this acceleration. To investigate further the effects of air exposure on epidermal barrier ontogenesis, we compared the activities of several key enzymes of lipid metabolism and gene expression of protein markers of epidermal differentiation in fetal rat skin explants grown immersed versus air exposed. The rate-limiting enzymes of cholesterol (HMG CoA reductase) and ceramide (serine palmitoyl transferase) synthesis were not affected. In contrast, the normal developmental increases in activities of glucosylceramide synthase and cholesterol sulfotransferase, responsible for the synthesis of glucosylceramides and cholesterol sulfate, respectively, were accelerated further by air exposure. Additionally, two enzymes required for the final stages of barrier maturation and essential for normal stratum corneum function, beta-glucocerebrosidase, which converts glucosylceramide to ceramide, and steroid sulfatase, which desulfates cholesterol sulfate, also increased with air exposure. Furthermore, filaggrin and loricrin mRNA levels, and filaggrin, loricrin, and involucrin protein levels all increased with air exposure. Finally, occlusion with a water-impermeable membrane prevented both the air-exposure-induced increase in lipid enzyme activity, and the expression of loricrin, filaggrin, and involucrin. Thus, air exposure stimulates selected lipid metabolic enzymes and the gene expression of key structural proteins in fetal epidermis, providing a biochemical basis for air-induced acceleration of permeability barrier maturation in premature infants.     

The Th2 cytokine,interleukin‐4, abrogates the cohesion of normal stratum corneum in mice: implications for pathogenesis of atopic dermatitis

There is mounting evidence that Th2 cytokines adversely affect skin barrier functions and contribute to the pathogenesis of atopic dermatitis (AD). AD is also characterized by abnormal cohesion in the stratum corneum (SC). However, the contribution of Th2 cytokines to this abnormality remains unknown. This study examined the effects of IL‐4, a prototypic Th2 cytokine, on the cohesion of the SC. Structural and physiological assessments revealed that repeated intradermal injections of IL‐4 compromised the cohesion of the SC of normal hairless mice. Two potential mechanisms were explored to account for the altered cohesion. First, IL‐4 decreased the amount of corneodesmosomes and down‐regulated the expression of desmoglein 1, but not of corneodesmosin (CDSN) or loricrin expression, in murine skin and in cultured human keratinocytes (KC). IL‐4 did not affect the skin surface pH, and in situ zymography revealed no net change in total serine protease activity in the IL‐4‐treated SC. Yet, IL‐4 enhanced expression of kallikrein (KLK)7, while simultaneously down‐regulating KLK5 and KLK14. Finally, IL‐4 did not alter the expression of the lympho‐epithelial Kazal‐type inhibitor (LEKTI) in KC. This study suggests that IL‐4 abrogates the cohesion of SC primarily by reducing epidermal differentiation.     

Course of macular edema in uveitis under medical treatment

OBJECTIVE: To describe the response of uveitic macular edema to various treatment methods using optical coherence tomography (OCT). METHODS: This is a prospective study of consecutive uveitis patients with macular edema in at least one eye. The patients received medical treatment. Best corrected Snellen Visual Acuity (BCVA) and tomographic features of the macula, including macular thickness measurement, were obtained at one, three, six, and 12 months after commencing treatment. RESULTS: Eighty-one eyes of 58 patients were analyzed. Complete resolution of macular edema occurred in 38 eyes (47%). The average BCVA was 20/34 logarithm of minimum angle of resolution (-logMAR, 0.2 +/- 0.3) upon study entry and 20/27 (-logMAR, 0.13 +/- 0.29) upon study completion. The difference was statistically significant (p = 0.04). The corresponding mean retinal thickness at the central fovea was 319 +/- 150 microm at the beginning of the study compared to 241 +/- 125 microm at 12 months (p < 0.001). A weak but statistically significant correlation between the reduction of macular thickness and the improvement of BCVA (r = 0.3, p = 0.01) was found. Thirteen of the 43 eyes (30%) with persistent macular edema had a more than 15% reduction of macular thickness compared to baseline, whereas 10 eyes (23, 3%) had a more than 15% increase in macular thickness. Statistical analysis indicated that the presence of an epiretinal membrane and an OCT pattern of diffuse macular edema was a significant factor associated with medical treatment failure. CONCLUSION: This study demonstrates the overall favorable visual prognosis of uveitic macular edema under medical treatment. The presence of an epiretinal membrane is an important factor associated with medical treatment failure.     

Oxysterol stimulation of epidermal differentiation is mediated by liver X receptor-beta in murine epidermis

Liver X receptor-alpha and -beta are members of the nuclear hormone receptor superfamily that heterodimerize with retinoid X receptor and are activated by oxysterols. In recent studies we found that treatment of cultured human keratinocytes with oxysterolstimulated differentiation, as demonstrated by increased expression of involucrin and transglutaminase, and inhibited proliferation. The aims of this study were to determine: (i) whether oxysterols applied topically to the skin of mice induce differentiation in normal epidermis; (ii) whether this effect is mediated via liver X receptor-alpha and/or liver X receptor-beta; and (iii) whether oxysterols normalize epidermal morphology in an animal model of epidermal hyperplasia. Topical treatment of normal hairless mice with 22(R)-hydroxycholesterol or 24(S),25-epoxycholesterol resulted in a decrease in epidermal thickness and a decrease in keratinocyte proliferation assayed by proliferating cell nuclear antigen staining. Moreover, oxysterol treatment increased the levels of involucrin, loricrin, and profilaggrin protein and mRNA in the epidermis, indicating that oxysterols stimulate epidermal differentiation. Additionally, topical oxysterol pretreatment improved permeability barrier homeostasis. Whereas liver X receptor-alpha-/- mice revealed no alterations in epidermal differentiation, the epidermis was thinner in liver X receptor-beta-/- mice than in wild-type mice, with a reduced number of proliferating cell nuclear antigen positive cells and a modest reduction in the expression of differentiation markers. Topical oxysterol treatment induced differentiation in liver X receptor-alpha-/- mice whereas in liver X receptor-beta-/- mice there was no increase in the expression of differentiation markers. Whereas both liver X receptor-alpha and liver X receptor-beta are expressed in cultured human keratinocytes and in fetal rat skin, only liver X receptor-beta was observed on northern blotting in adult mouse epidermis. Finally, treatment of hyperproliferative epidermis with oxysterols restored epidermal homeostasis. These studies demonstrate that epidermal differentiation is regulated by liver X receptor-beta and that oxysterols, acting via liver X receptor-beta, can induce differentiation and inhibit proliferation in vivo. The ability of oxysterols to reverse epidermal hyperplasia suggests that these agents could be beneficial for the treatment of skin disorders associated with hyperproliferation and/or altered differentiation.     

彩色多普勒超声检测自体肾和移植肾的肾动脉狭窄

目的 探讨彩色多普勒超声在检测自体肾和移植肾肾动脉狭窄(RAS)中的价值和局限性。方法 回顾性对照分析了临床可疑RAS的30例自体肾和14例移植肾的彩色多普勒超声(US)与磁共振动脉造影(MRA)及动脉血管造影的结果。并将狭窄肾动脉扩张／再通术前后的肾动脉血流速度，肾内小动脉多普勒波形特征(升速时间-AT，升速指数-AI，阻力指数-RI)进行了比较。结果 30例自体肾RAS的超声诊断中有2例假阳性和2例假阴性。14例移植肾RAS阳性的超声检查无误差。肾动脉血流速度和肾内小动脉的多普勒波形在RAS纠正术前后有显著改变。结论 尽管彩色多普勒超声在检测RAS中有局限性，其仍被列为对可疑RAS病例的初步影像检查，并在观测随访RAS纠正术后的肾血流灌注及狭窄复发中有重要作用。综合分析肾动脉及肾内动脉的血流速度和多普勒波形特征并参考有关临床资料有助于提高超声诊断RAS的准确性。     

Effects of SCH 23390 and sulpiride on the behaviors evoked by amphetamine and apomorphine in adult cats

Motles Elias, Ariel Gomez, Montserrat Tetas and Magali Gonzalez: Effects of SCH 23390 and Sulpiride on the Behaviors Evoked by Amphetamine and Apomorphine in Adult Cats. Prog. Neuro — Psychopharmacol. & Biol. Psychiat. 1993, 17(6): 1005–1022.

1. 1. The aim of the present study was to analyze whether the dopaminergic D1 and D2 receptors are involved in the production of the behaviors evoked by parenteral administration of amphetamine and apomorphine in adult cats.

2. 2. Fifteen mongrel cats of both sexes were injected, in separate sessions, with 2.5 mg/kg of amphetamine and 2.0 mg/kg of apomorphine. The D1 receptor blocker, SCH 23390 was administered (0.3 mg/kg i.p.) and after 60 min, amphetamine and apomorphine were again injected on different days. The same procedure was carried on with sulpiride in two doses (20 and 30 mg/kg i.p.). The behaviors induced by the two dopaminergic drugs, before and after the receptor blocker administration were respectively compared. The Wilcoxon signed rank test was employed for statistical analysis. Three independent observers recorded the behaviors.

3. 3. SCH 23390 and sulpiride produced per se hypomotility and sedation, effects that were considered when analysing the results. Some of the behaviors produced by amphetamine (pupillary dilation, head movements) were slightly modified by both receptor blockers. SCH 23390 only modified the licking behavior produced by apomorphine. In contrast, sulpiride blocked almost all the behaviors elicited by apomorphine, especially when the 30 mg/kg dose was administered. It is concluded that the behaviors produced by the 2 mg/kg dose of apomorphine are evoked by its binding to the post — synaptic dopaminergic D2 receptors and blocked by sulpiride.