[Agreement between clinical evaluation, Heidelberg-Retina-Tomograph (HRT) and Nerve Fiber Analyzer (GDx) in glaucoma diagnosis]. / Ubereinstimmung von klinischer Beurteilung, Heidelberg-Retina-Tomograph (HRT) und Nerve Fiber Analyzer (GDx) in der Glaukomdiagnostik.

BACKGROUND: We have made a comparison of clinical evaluation, Heidelberg-Retina-Tomograph (HRT) and Nerve Fiber Analyzer (GDx) in diagnosing glaucoma. MATERIALS AND METHODS: One eye of 38 glaucoma patients and 26 non-glaucoma patients was examined with HRT and GDx. Assignment of the patients into the two groups by clinical evaluation was performed on the basis of visual field and optic disc results. As classification criterion for glaucoma/non-glaucoma by means of the instruments we employed the statistical classification of the HRT and "the number" of the GDx. Statistical analysis was performed with Cohen's kappa and McNemar tests. Additionally, ROC curves for evaluation of the sensitivity and specificity of the glaucoma classification are demonstrated for HRT and GDx. RESULTS: Agreement between clinical evaluation and HRT was moderate (Cohen's kappa = 0.43), there was no significant over- or underdiagnosis by HRT (p = 0.48). Agreement between clinical evaluation and GDx (diagnosis of glaucoma when "the number" > 50) was bad (Cohen's kappa = 0.27) with a significant overdiagnosis by GDx compared to clinical evaluation (p < 0.05). Agreement between clinical evaluation and GDx (diagnosis of glaucoma when "the number" > 40) was better (Cohen's kappa = 0.54), there was no significant over- or underdiagnosis by GDx (p = 0.79). ROC curves for glaucoma classification showed no difference between HRT and GDx (area under the curve: HRT = 0.8, GDx = 0.78). CONCLUSIONS: Because of the only moderate agreement between clinical evaluation on the one hand and HRT and GDx classification on the other hand for the discrimination between glaucoma and non-glaucoma, the clinician should not completely rely on the instrument-derived glaucoma classification.

Ocular pulse amplitude in patients with open angle glaucoma, normal tension glaucoma, and ocular hypertension.

BACKGROUND/AIM: Intraocular pressure (IOP) is not a fixed constant value but rather has pulsatile components associated with cardiac action. The SmartLens dynamic observing tonometer (odc, Ophthalmic Development Company AG, Zurich, Switzerland) can measure and record simultaneously IOP and ocular pulse amplitude (OPA). It was the aim of this study to evaluate OPA in patients with primary open angle glaucoma (POAG) and high IOP, normal tension glaucoma (NTG), and ocular hypertension (OHT). Furthermore, the authors examined whether there were any correlations with blood pressure. METHODS: 80 subjects were divided into four groups (n=20): 20 patients each with POAG, NTG, and OHT and 20 volunteers without any ocular pathology except for cataract served as a control group. RESULTS: The OPA of the POAG group was not statistically significant different from the control group and from the OHT group. However, OPA was statistically significant lower (p<0.01) in the NTG group compared with all other groups. The OPA of the OHT group was slightly higher compared to the healthy volunteers (p=0.09) and to the POAG patients (p=0.09). No statistically significant correlations with blood pressure could be detected. A logistic regression model was established which identified OPA as an independent risk factor for NTG. CONCLUSIONS: The study demonstrated a decrease in OPA of patients suffering from NTG. Thus, measuring of OPA by the SmartLens dynamic observing tonometer could be helpful in the detection of NTG patients.

[Results of implantation of a Worst Iris Claw Lens for correction of high myopia]. / Ergebnisse nach Implantation einer Worst Iris Claw Lens zur Korrektur der hohen Myopie.

BACKGROUND: The purpose of this clinical study was to evaluate refraction, best visual acuity and anterior chamber flare after implantation of a Worst Iris Claw Lens to correct high myopia. PATIENTS AND METHODS: From September 1996 to February 1999 the implantation of a Worst Iris Claw lens was performed on 44 highly myopic phakic eyes of 28 patients. Data after 6 weeks and 6 months follow-up were assessed. RESULTS: The mean preoperative spherical equivalent was--17.35 +/- 3.57 dpt and 6 months after implantation 79% of the eyes were within +/- 1.0 dpt of target refraction. The mean best corrected visual acuity increased from 0.43 preoperatively to 0.65 postoperatively and 6 months after the treatment there was no flare (< 10 photons/ms) in 21% and a mild anterior chamber flare (10-80 photons/ms) in 76% of the treated eyes. The median laser flare was 20 p/ms. CONCLUSIONS: In conclusion, implantation of a Worst Iris Claw lens has proved to be a precise method to correct high myopia. No or mild anterior chamber flare and a good visual acuity were measured in most eyes 6 weeks and 6 months after surgery. Longer follow-up periods are needed to assess the long-term safety and efficiency.

Drug expenditure in hospitals: what do German ward physicians know?

AIMS: Ward physicians hold key positions in the course of efforts to reduce drug expenditures in hospitals. This study evaluated the knowledge of German hospital physicians with respect to the daily therapeutic costs of 21 frequently used drugs. METHODS: A questionnaire survey was carried out among 168 ward physicians from university and municipal hospital departments of internal medicine. RESULTS: One hundred and twenty-seven physicians returned a completed questionnaire, a response rate of 75.6%. On average the physicians successfully identified both low cost and expensive drugs. The prices of inexpensive and moderately expensive drugs were generally overestimated whereas those for the expensive and highly expensive drugs were underestimated in 35% and 68% of respondents, respectively. CONCLUSIONS: The results of this survey of German hospital physicians suggest that a more economically efficient use of drugs could be achieved by an improved knowledge of daily therapeutic costs.

Clinical comparison of two intraocular pressure measurement methods: SmartLens dynamic observing tonography versus Goldmann.

PURPOSE: To compare intraocular pressure measurements obtained with SmartLens, a gonioscopic contact lens, to those from Goldmann applanation tonometry. METHODS: Eighty volunteers (20 healthy individuals and 60 glaucoma patients from the university eye hospital's outpatient department) were examined using conventional Goldmann tonometry and the new SmartLens tool. For each device three replicate measurements were performed. A paired t-test and the corresponding mean difference confidence interval approach were used to assess deviations in location of the two tonometric methods; the test procedure of Maloney and Rastogi was used for comparison of precision in paired data. Intraindividual differences were evaluated according to the approach of Altman and Bland. RESULTS: There was a mean difference of 5.6 mmHg (95% CI: 4.3 mmHg; 6.8 mmHg; P<0.01) in intraocular pressure between the two methods with a significant overestimation by SmartLens tonometry compared to Goldmann tonometry (P<0.01). The 95%-limits of agreement ranged from -5.4 mmHg to +16.6 mmHg for individual patients. The measurement method variance of SmartLens was higher (Maloney-Rastogi test; P <0.01). The mean coefficients of variation for intraindividual replicates were 10.1% (SmartLens) and 3.8% (Goldmann; P <0.01). CONCLUSIONS: Accepting Goldmann tonometry as gold standard for intraocular pressure measurement, the SmartLens method shows considerable variation and therefore is not proven to be an adequate substitute for Goldmann tonometry.

Normal oxidative stress and enhanced lipoprotein resistance to in vitro oxidation in hypertriglyceridemia: effects of bezafibrate therapy.

Although there is evidence that hyperlipidemia and predominance of small dense low density lipoproteins (LDLs) are associated with increased oxidative stress, the oxidation status in patients with hypertriglyceridemia (HTG) has not been studied in detail. Therefore, we studied urinary levels of F(2)-isoprostanes (8-isoprostaglandin F(2alpha) and 2,3-dinor-5,6-dihydro-8-isoprostaglandin F(2alpha)) and susceptibility of very low density lipoproteins (VLDLs) and LDLs to oxidation ex vivo in 18 patients with endogenous HTG and 20 matched control subjects. In addition, the effects of 6 weeks of bezafibrate therapy were assessed in a double-blind, placebo-controlled, crossover trial. Urinary levels of F(2)-isoprostanes were similar in the HTG and normolipidemic group. Bezafibrate caused an increase in 8-isoprostaglandin F(2alpha) (762+/-313 versus 552+/-245 ng/24 h for bezafibrate and placebo therapy, respectively; P=0.03), whereas 2,3-dinor-5, 6-dihydro-8-isoprostaglandin F(2alpha) levels tended to be increased (1714+/-761 versus 1475+/-606 ng/24 h for bezafibrate and placebo therapy, respectively; P=0.11). VLDLs and LDLs were more resistant to copper-induced oxidation in patients with HTG than in control subjects. Bezafibrate reversed the oxidation resistance to the normal range. In conclusion, these results indicate the following: (1) HTG is associated with normal in vivo oxidative stress and enhanced ex vivo resistance of lipoproteins to oxidation. (2) Bezafibrate reduces the resistance of lipoproteins to copper-induced oxidation and enhances oxidative stress in HTG patients.

Nebivolol decreases systemic oxidative stress in healthy volunteers.

AIMS: Nebivolol is a selective, vasodilatory beta1-adrenergic receptor antagonist which has been suggested to possess additional antioxidative properties. The aim of the present study was to assess the actions of nebivolol in antihypertensive doses on systemic oxidative stress in healthy volunteers, reflected by 24 h urinary excretion of 8-iso-PGF2alpha. METHODS: In a double-blind, cross-over study, 12 healthy volunteers received 5 mg nebivolol once daily or placebo for a total of 7 days, separated by a wash out period of 2 weeks. After each treatment period 24 h urinary excretion of 8-iso-PGF2alpha was determined by gas chromatography-tandem mass spectrometry. RESULTS: After the 7 day treatment period nebivolol decreased significantly urinary excretion of 8-iso-PGF2alpha by 24% from 55.3 +/- 5.1 pmol mmol-1 creatinine during the placebo period to 42.3 +/- 4.7 pmol mmol-1 creatinine (mean +/- s.e. mean, P = 0. 01), a mean decrease of 13 pmol mmol-1 creatinine (95% CI: -22.8; -3. 1). CONCLUSIONS: Our data show for the first time that nebivolol decreases systemic oxidative stress in young healthy volunteers.

The IL-1 system in psoriatic skin: IL-1 antagonist sphere of influence in lesional psoriatic epidermis.

The epidermal expression of IL-1 in psoriasis is clearly altered, but data are still incomplete and poorly understood. To thoroughly study the IL-1 system in psoriasis, we semiquantitatively analyzed the expression of all currently characterized IL-1 isoforms and their receptors in parallel in both lesional (PP) and nonlesional psoriatic (PN) epidermis. Immunostaining of skin sections showed that IL-1alpha, located in the basal keratinocytes of normal control (NN) and PN epidermis, was significantly decreased to negligible levels in PP epidermis. IL-1 receptor antagonist (IL-1ra) and IL-1R type II (IL-1RII) were both significantly overexpressed in mutually exclusive compartments of PP epidermis, the suprabasal and basal compartment, respectively. A significant inverse correlation was found between the expressions of IL-1alpha and these two IL-1 antagonists, which may be inherent to the accelerated terminal differentiation of the psoriatic keratinocyte. In situ hybridization of IL-1(R) mRNAs confirmed the staining results. Levels of IL-1ra mRNA, however, were not increased in PP epidermis, suggesting that the overexpression of IL-1ra protein may be explained at the level of translation. The more sensitive PCR demonstrated a clearly increased expression of IL-1beta mRNA in PP epidermal cells (EC), which may be related to the inflammatory response in psoriasis. IL-1RI mRNA was clearly present in both PP and NN EC. The mRNA levels of the secreted IL-1ra isoform, but not intracellular IL-1raI and II, and IL-1RII were elevated in PP EC and paralleled those of IL-1beta. In summary, this study provides a defined phenotype of the complete epidermal IL-1 system in psoriasis; it shows that the expressions of IL-1(R) isoforms are coordinately altered, resulting in a predominance of IL-1 antagonists, which may represent a negative feedback response to IL-1 agonists, leading to a decreased IL-1 responsiveness.

Allergy to carbamazepine: parallel in vivo and in vitro detection.

PURPOSE: Five to 20% of patients discontinue antiepileptic drug (AED) therapy because of adverse reactions. Careful reintroduction, however, may be considered if true drug allergy can be ruled out. Definitive assessment of such immunologically mediated reactions requires demonstration of either specific antibodies or sensitized lymphocytes. METHODS: We investigated whether skin patch tests (PTs) and in vitro lymphocyte proliferation assays (LPAs) were suitable for detection of allergy to carbamazepine (CBZ) and the possibly cross-reactive oxcarbazepine (OCBZ). Data of 65 patients displaying a wide range of possibly allergic side effects to CBZ were available for analysis. Data of CBZ users without any side effects and healthy volunteers served as controls. Both PTs and LPAs were done with CBZ, OCBZ and three metabolites [CBZ-10,11-epoxide (CBZ-E), 10-monohydroxy-CBZ (MHD), and 10,11-dihydroxy-CBZ (DIOL)]. RESULTS: Positive PTs with CBZ were seen in 20% and with OCBZ in 14% of the patients. Positive LPA results with CBZ and OCBZ, respectively, were found in 40 and 19%. Both tests were positive in 14 and 7% of the patients. Cross-reactivity to OCBZ was seen in -40% of CBZ-reactive patients in both PTs and LPAs. CONCLUSION: These data illustrate the additional value of LPAs in the detection of CBZ allergy while showing that a major part of side effects to CBZ and OCBZ is not immunologically mediated, according to PTs and LPAs.

Exfoliative dermatitis due to immunologically confirmed carbamazepine hypersensitivity.

A 6-year-old Caucasian girl experienced a generalized erythematous skin rash during carbamazepine therapy. Over the next four days the eruption worsened into erythroderma with fever and generalized lymphadenopathy. Routine laboratory studies revealed increased serum levels of liver enzymes and eosinophilia. Immunologic reactivity to the anticonvulsant carbamazepine and its analogs was investigated both in vivo and in vitro by patch tests and lymphocyte proliferation assays, respectively.

Suggestive evidence for bromocriptine-induced pleurisy.

Pleurisy of initially unknown origin was found in a patient who was treated with bromocriptine for Parkinson's disease for 6 years. At presentation, bilateral pleural thickening existed that caused severe restriction of pulmonary function. There were an elevated erythrocyte sedimentation rate, polyclonal hypergammaglobulinaemia, increased levels of acute phase proteins and anaemia. After withdrawal of the bromocriptine the patient's complaints as well as the laboratory parameters markedly improved. Further loss of pulmonary function did not occur. However, the pleural thickening did not resolve, not even upon subsequent corticosteroid treatment, probably due to fibrosis. Together, these findings strongly suggest a causative role of bromocriptine. The results of the laboratory studies suggested an immunopathogenetic mechanism, but in vitro lymphocyte-proliferation studies and skin patch tests with bromocriptine were negative. Bromocriptine should be considered as a cause of pleurisy. The drug must be stopped immediately upon the occurrence of pleural thickening in order to prevent impairment of pulmonary function. In addition, periodic laboratory and X-ray studies in patients on long-term bromocriptine treatment should be considered.

Increased expression of interleukin-4 receptors on psoriatic epidermal cells.

Abnormal keratinocyte proliferation and differentiation, the main characteristics of psoriasis, may be induced and maintained by cytokines produced by activated resident and recruited inflammatory cells in lesional skin. As the epidermal cytokine profile is clearly altered in psoriasis and because increased expression of interleukin-4 receptor (IL-4R) has been reported in some epithelial proliferative diseases, we investigated the expression of IL-4R on psoriatic epidermal cells (ECs). The expression of IL-4R on freshly isolated ECs from healthy skin and untreated psoriatic lesions was studied by immunostaining using an IL-4R-specific antibody and by examining their capacity to bind biotinylated recombinant human IL-4 using flow cytometry. The number of IL-4R+ ECs and the number of binding sites per cell were significantly increased on psoriatic ECs as compared with healthy control ECs. Immunostaining confirmed these results, whereby staining was mainly observed in the lower epidermal layers. In addition, an increased IL-4R mRNA expression was also observed in psoriatic epidermis using a digoxigenin-labeled IL-4R RNA probe. In short-term in vitro cultures, lipopolysaccharide/phorbol-myristate-acetate-stimulated and unstimulated psoriatic ECs did not produce any immunoreactive IL-4. The results of this study together with the reported increased expression of IL-4R in epithelial neoplasias suggest an association between overexpression of IL-4R and abnormal keratinocyte activation and proliferation.

Diurnal variation of corticotropin-releasing factor binding sites in the rat brain and pituitary.

1. Corticotropin-releasing factor (CRF) is thought to be involved in the regulation of the diurnal activity of the hypothalamus-pituitary-adrenal (HPA) axis and to act as a neurotransmitter in the brain. To date it is unknown whether the binding sites of the central CRF system are subject to diurnal variations. 2. We measured the number of CRF binding sites over the course of a complete 24-hr light-dark cycle in the pituitary, amygdala, bed nucleus of the stria terminalis (BNST), cingulate cortex, visceral cortex, paraventricular nucleus of the hypothalamus, hippocampus, and locus ceruleus of rats by in vitro receptor autoradiography with iodinated ovine CRF. A 24-hr time course was also established for plasma CRF and corticosterone. 3. The diurnal pattern of plasma CRF does not correlate with the pattern of plasma corticosterone. Within the brain, CRF binding in the basolateral nucleus of the amygdala showed a U-shaped curve with maximum levels in the morning and a wide hallow between 1500 and 0100. A biphasic profile with a small depression in the afternoon and a more pronounced depression in the second half of the activity period is characteristic for the other brain areas and the pituitary. The profile for the pituitary correlates with those for the BNST and the area of the locus ceruleus. Furthermore, the diurnal pattern of CRF binding sites in the BNST correlates with that of the hippocampus, and the daytime pattern of the visceral cortex is similar to that of both the hippocampus and the BNST. 4. Since the CRF-binding profiles in the brain and the pituitary clearly differ from the profiles of both plasma CRF and corticosterone, one may assume that the diurnal pattern of central CRF binding sites is not directly coupled to the activity of the HPA axis.

Enhanced production of biologically active interleukin-1 alpha and interleukin-1 beta by psoriatic epidermal cells ex vivo: evidence of increased cytosolic interleukin-1 beta levels and facilitated interleukin-1 release.

The expression of interleukin (IL)-1 is altered in psoriatic lesions. However, little is known about the actual production of IL-1 alpha and IL-1 beta by psoriatic epidermal cells (EC). We monitored IL-1 in the extracellular, the membrane and the intracellular compartment of freshly isolated EC from untreated lesional psoriatic (PP) and normal healthy (NN) skin during non-stimulated short-term cultures, representing a psoriasis model ex vivo. Cytokines were measured using bioassays combined with neutralizing antibodies and enzyme-linked immunosorbent assay in parallel. PP EC released significantly increased amounts of biologically active IL-1 alpha and IL-1 beta in a ratio of 3:1, whereas NN EC only released IL-1 alpha. Also, the release of IL-6, but not of TNF-alpha, by PP EC was significantly increased. Membrane-associated IL-1 activity, analyzed using glutaraldehyde-fixed EC, was low and not unique to PP EC. The cytosol of PP EC contained significantly increased levels of immunoreactive IL-1 beta. Furthermore, PP EC displayed loss of membrane integrity, as determined by trypan blue exclusion and release of cytosolic lactate dehydrogenase. This facilitated release of intracellular IL-1. Depletion of CD45+ cells showed that intraepidermal leukocytes did not contribute to the production of IL-1. Our observations show that resident PP EC express enhanced IL-1 production ex vivo, which is due to an increased cytosolic IL-1 beta content and facilitated IL-1 release. This study provides the first evidence that PP EC can produce bioactive IL-1 beta.

Hyposensitization in nickel allergic contact dermatitis: clinical and immunologic monitoring.

BACKGROUND: In allergic contact dermatitis (ACD) previously sensitized T cells cause skin damage. If an ubiquitous allergen such as nickel is involved, no effective treatment is available. Down-regulation of this allergic response has been described after antigen presentation in the absence of adequate costimulatory signals. UV exposure can enhance such hyposensitization. OBJECTIVE: The aim of this study was to establish the capability of a hyposensitization procedure to induce antigen-specific tolerance. METHODS: Twenty-one patients with nickel ACD were randomly assigned to either a hyposensitized or control group. A schedule consisting of UVB treatment and subcutaneous nickel sulfate administration (hyposensitization) or UVB only (control) was applied. During the ensuing 2 years, several clinical and immunologic features were monitored. RESULTS: During UVB treatment we observed a significant clinical improvement in both groups that persisted in the hyposensitized group. Except for increased slope variances of specific lymphocyte proliferation in time, no clear changes were seen in the immunologic findings. CONCLUSION: Despite significant clinical improvement induced by UVB, hyposensitization did not induce significant changes in the immunologic findings in patients with nickel ACD.

Cyclosporine in atopic dermatitis. Modulation in the expression of immunologic markers in lesional skin.

BACKGROUND: In previous studies, oral cyclosporine was highly effective in the treatment of patients with severe atopic dermatitis. In this study seven patients with severe and therapy-resistant atopic dermatitis underwent therapy with cyclosporine, 5 mg/kg/day, for 6 weeks. OBJECTIVE: The effect of cyclosporine on the expression of cytokines, which probably play a role in this disease, was examined. METHODS: The study was performed with a panel of antibodies as markers of inflammatory cells, adhesion molecules, and cytokines (interferon-gamma [IFN-gamma], tumor necrosis factor-alpha [TNF-alpha] and interleukins 1 alpha, 1 beta, and 8 [IL-1 alpha, IL-1 beta, and IL-8, respectively]). They were visualized by indirect immunoperoxidase techniques. RESULTS: After 2 weeks of cyclosporine therapy, a reduction of 60% in the disease (severity and extent) was observed. This reduction was 89% after 4 weeks and 90% after 6 weeks of therapy. Results of indirect immunoperoxidase stains performed on lesional skin sections after 2 weeks of treatment showed statistically significant reduced numbers of CD14+, CD25 (IL-2R+) and IL-8+ inflammatory cells in the dermis and CD36(OKM5)+ cells in both the epidermis and dermis. The number of cells expressing IFN-gamma and TNF-alpha, assumed to be the products of the helper T-cell (TH)1 subset, was unaltered despite the impressive clinical benefit observed. Keratinocytes in lesional atopic skin did not express intercellular adhesion molecule type 1 (ICAM-1). The expression of the adhesion molecules ICAM-1, lymphocyte function-associated (LFA) type 1, and LFA-3 on inflammatory cells also remained unaffected by cyclosporine treatment. CONCLUSION: A statistically significant reduction in the number of activated T cells and in the number of cells expressing the IL-2 receptor (CD25) paralleled a marked improvement in the disease and supports the view that atopic dermatitis is based on a T-cell-mediated immune inflammation.