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To study the effect of weaning age on average daily gain (ADG), dry matter intake (DMI) and ruminal fermentation, 10 rumen-cannulated male Holstein calves were randomly assigned to one of two treatments: (i) early weaned at 8 weeks of age (235 l milk); (ii) conventionally weaned at 12 weeks of age (347 l milk). Twice daily grass hay (9.0 MJ ME x kg(-1) DM) and a dry total mixed ration (TMR) (11.6 MJ ME x kg(-1) DM) containing 15% alfalfa hay and 85% concentrates were offered separately. Water was available ad libitum. Ruminal fluid was collected via cannulas at weeks 9, 11, 13 and 15, twice weekly just prior to as well as 1, 3, 5 and 7 h after morning feeding. Calves of both treatments achieved adequate ADG (947 vs. 959 g; p > 0.05). Just-weaned calves rapidly increased DMI (1.1-2.5 kg TMR and 2.4-3.6 kg TMR for early- and conventionally-weaned calves, respectively). From weeks 10-12 early-weaned calves consumed significantly more dry feed than conventionally-weaned calves (week 10: 2.5 vs. 1.6 kg/d; week 12: 3.4 vs. 2.4 kg/d). Early weaning stimulates DMI supporting ruminal fermentation intensity, indicated by lower ruminal pH. After weaning, only early-weaned calves achieved critical average ruminal pH (week 9: 5.7 vs. 6.0, p = 0.017; week 11: 5.9 vs. 6.2, p = 0.007). Experimental treatment did not affect the concentration of ruminal short-chain fatty acids (SCFA). For all calves, the effects of the concentrate-rich TMR were shown by a high SCFA level (daily average: 137-152 mmol x l(-1)) and an acetate to propionate to butyrate ratio between 51:36:9 and 54:33:10.

In-situ measurement of fallout radionuclides (137)Cs and (210)Pb(ex) has the potential to assess soil erosion and sedimentation rapidly. In this study, inventories of (137)Cs and (210)Pb(ex) in the soil of Inner Mongolia grassland were measured using an In-situ Object Counting System (ISOCS). The results from the field study indicate that in-situ gamma-ray spectrometry has the following advantages over traditional laboratory measurements: no extra time is required for sample collection, no reference inventories are required, more economic, prompt availability of the results, the ability to average radionuclide inventory over a large area, and high precision., (Copyright 2010 Elsevier Ltd. All rights reserved.)

We report on the first detailed comparison of evaluation results regarding the correct billing in the G-DRG (German diagnosis-related group) system. For two Medical Review Boards of the Statutory Health Insurance Funds of comparable size (MDK Baden-Württemberg and MDK Westfalen-Lippe), we analysed consecutive expertises regarding correct billing according to section sign 275 SGB V, and the results were compared in terms of the frequency of DRG-relevant error codes, their relevance to revenue, and the question of error clustering (specific DRGs, primary diagnoses, etc.). The analysis comprised 51,010 individual expertises pertaining to billings of the year 2005 (admittance to hospital from January 1 to December 31, 2005). The proportion of disapproved cases was 38.5% in Baden-Württemberg and 44.6% in Westfalen-Lippe. Among these, errors to the disadvantage of the Health Insurance (incorrectly high) were 33.9% and 39.3%, respectively, and errors to the disadvantage of the hospitals (incorrectly low) were 4.6% and 5.3%, respectively. The resulting ratio (incorrectly high vs. low) was an identical 7.4 in both cases. Not only the most commonly rejected DRGs but also the primary and secondary diagnoses were similar in both cases, while the disapproved procedure codes showed a significant variability (analysis based on the respective 10 most common objections). We discuss the similarities and differences in these results and their possible causes, and demonstrate the cost relevance of this audit segment. Result comparisons of this type can yield insights into streamlining of the review practice of Medical Review Boards, as well as increase the efficiency and effectiveness of the selection of cases.

This paper examines the need, feasibility, and validity of combining two biometric (urine and saliva) and three self-report (recency, peak quantity, and frequency) measures of substance use for marijuana, cocaine, opioids, and other substances (including alcohol and other drugs). Using data from 337 adults with substance dependence, we used structural equation modeling to demonstrate that these multiple measures are driven by the same underlying factor (substance use) and that no single measure is without error. We then compared the individual measures and several possible combinations of them (including one based on the latent factors and another based on the Global Appraisal of Individual Needs (GAIN) Substance Frequency Scale) to examine how well each predicted a wide range of substance-related problems. The measure with the highest construct validity in these analyses varied by drug and problem. Despite their advantages for detection, biometric measures were frequently less sensitive to the severity of other problems. Composite measures based on the substance-specific latent factors performed better than simple combinations of the biometric and psychometric measures. The Substance Frequency Scale from the GAIN performed as well as or better than all measures across problem areas, including the latent factor for any use. While the research was limited in some ways, it has important implications for the ongoing debate about the proper way to combine biometric and psychometric data.

Background: According to the scientific literature, a hearing impairment which is acquired late reduces mental efficiency., Objective: To determine by empirical examination whether hearing aids increase mental efficiency. PERSONS AND METHODS: An open controlled application study was carried out on the capacity of working memory in 15 first users of hearing aids., Results: The working memory's capacity in the 15 users (age: 72+/-12 years; six females; crystallized IQ: 100+/-13; test-retest period: 74+/-35 days) increased 13+/-19% (IQ-increment 3.4+/-6.3 points), while the capacity of the 15 controls (age: 71+/-11 years; seven females; crystallized IQ: 103+/-12; test-retest period: 58+/-21 days) remained unchanged: 0+/-12% (IQ-change: -0.3+/-5.1 points). The difference between the samples is significant (p=0.012 one-tailed). The visually and auditively administered subtests yielded equal changes. According to self-reports, the daily wearing time was 6.7+/-3.5 h. Daily wearing times of the hearing aids (self-reports) of between 4-8 h showed the multiple IQ-gain compared to lesser or longer times. The audiometric gain in hearing without noise on the right (rho=0.58; significant), left (0.48; not significant), and on both sides (0.68; significant) correlated with IQ-gain., Conclusions: Under a more favourable usage a still more striking benefit is to be expected in mental efficiency.

The adrenal cortex is a major stress organ in mammals that reacts rapidly to a multitude of external and internal stressors. Adrenocorticotropin (ACTH) is the main stimulator of the adrenal cortex, activating corticosteroid synthesis and secretion. We evaluated the mechanism of action of ACTH on adrenals of male rats, preserving the architecture of the gland in vitro. We demonstrated that both sodium nitroprusside (NP), a nitric oxide (NO) donor, and ACTH stimulate corticosterone release. NO mediated the acute response to ACTH because Nomega-nitro-l-arginine methyl ester, a NO synthase inhibitor, and hemoglobin, a NO scavenger, blocked the stimulation of corticosterone release induced by ACTH. NP stimulated prostaglandin E release, which in turn stimulated corticosterone release from the adrenal. Additionally, indomethacin, which inhibits cyclooxygenase, and thereby, prostaglandin release, prevented corticosterone release from the adrenal induced by both NP and ACTH, demonstrating that prostaglandins mediate acute corticosterone release. Corticosterone content in adrenals after incubation with ACTH or NP was lower than in control glands, indicating that any de novo synthesis of corticosterone during this period was not sufficient to keep up with the release of the stored hormone. The release induced by ACTH or NP depleted the corticosterone content in the adrenal by approximately 40% compared with the content of glands incubated in buffer. The mechanism of rapid release is as follows: NO produced by NO synthase activation by ACTH activates cyclooxygenase, which generates PGE(2), which in turn releases corticosterone stored in microvesicles and other organelles.

While addiction is increasingly recognized as a chronic condition, little information is available on the actual duration of addiction and treatment careers. The purpose of this study was to estimate the duration and correlates of years between (a) first use and at least a year of abstinence and (b) first treatment admission and at least one year of abstinence. Data are from 1,271 of 1,326 (96%) people recruited from a stratified sequential sample of admissions to publicly funded treatment programs in a large metropolitan area. Participants were interviewed at 6, 18, 24, 36, 48, and 60 months post-intake. With an average age at the referent intake of 35 (SD = 8) years, the sample is 59% female, 87% African American, 7% Hispanic, and 5% white. The most common dependence diagnoses were for cocaine (64%), alcohol (44%), opioids (41%), and/or marijuana (14%). Using lifetime substance use and treatment histories collected at intake and subsequent treatment utilization recorded during follow-up interviews, we conducted survival analysis to estimate the time from first use and first treatment until people reported 12 months of abstinence or died (with people still using, in treatment, or dead at the last follow-up treated as right censored). During the three years after intake, 47% reached at least 12 months of abstinence. The median time from first to last use was 27 years. The median time from first treatment episode to last use was 9 years. Years to recovery were significantly longer for males, people starting use under the age of 21 (particularly those starting under the age of 15), people who had participated in treatment 3 or more times, and for people high in mental distress. The exploratory results suggest that multiple episodes of care over several years are the norm and that rather than thinking of multiple episodes in terms of "cumulative dosage," it might be better thought of as further evidence of chronicity and that we need to develop and evaluate models of longer term recovery management.

Aims: To examine the comparability, reliability and predictive validity of two instruments used to assess alcohol use and dependence: the Global Appraisal of Individual Needs (GAIN) and the Form 90 Timeline Followback (TLFB) method., Design, Setting and Participants: Adolescents (n = 101) admitted to a residential treatment program in the United States were interviewed at intake with the GAIN, and again within a week with a variation of TLFB, called Form 90. Alcohol and cannabis measures were compared and used to predict the number of past-month substance abuse and dependence symptoms., Measurement: Self-report measures of days of alcohol and cannabis use in the 90 days prior to intake, peak number of drinks/joints used, peak blood alcohol content (BAC) and alcohol and cannabis abuse and dependence symptom counts., Findings: Results revealed that the measures had: (a) excellent comparability (r = 0.7-0.8) across the two instruments; (b) deteriorating reliability after reported peak BAC levels exceeded 0.50 and peak joints exceeding 19; and (c) similar and strong relationships between use measures and the number of abuse/dependence symptoms across measures and instruments., Conclusions: In a sample of 101 adolescents who were admitted to residential treatment for alcohol or drug dependence, the corresponding measures from the two instruments produced comparable results. If the cross-validation of these two measures generalizes to adolescents treated in out-patient settings and other adolescent treatment populations, the GAIN and Form 90 may provide useful core alcohol measures for meta-analyses.

This article presents the main outcome findings from two inter-related randomized trials conducted at four sites to evaluate the effectiveness and cost-effectiveness of five short-term outpatient interventions for adolescents with cannabis use disorders. Trial 1 compared five sessions of Motivational Enhancement Therapy plus Cognitive Behavioral Therapy (MET/CBT) with a 12-session regimen of MET and CBT (MET/CBT12) and another that included family education and therapy components (Family Support Network [FSN]). Trial II compared the five-session MET/CBT with the Adolescent Community Reinforcement Approach (ACRA) and Multidimensional Family Therapy (MDFT). The 600 cannabis users were predominately white males, aged 15-16. All five CYT interventions demonstrated significant pre-post treatment during the 12 months after random assignment to a treatment intervention in the two main outcomes: days of abstinence and the percent of adolescents in recovery (no use or abuse/dependence problems and living in the community). Overall, the clinical outcomes were very similar across sites and conditions; however, after controlling for initial severity, the most cost-effective interventions were MET/CBT5 and MET/CBT12 in Trial 1 and ACRA and MET/CBT5 in Trial 2. It is possible that the similar results occurred because outcomes were driven more by general factors beyond the treatment approaches tested in this study; or because of shared, general helping factors across therapies that help these teens attend to and decrease their connection to cannabis and alcohol.

Comparisons of well-developed practice-based interventions with research-based interventions are rare. This quasi-experimental study compares the outcomes of 274 adolescents (75% male; 63% weekly+ users; 54% dependent; 27% prior treatment; 73% with co-occurring problems) who received Chestnut Health System's best-practice Outpatient Treatment (CHS) or Cannabis Youth Treatment (CYT) research-based interventions. Ninety-five percent of participants completed follow-up interviews at three, six, nine, and 12 months after their intake GAIN interview. Initially, the CYT cohort scores indicated greater severity on several substance-related measures, while the CHS cohort scored higher on prior mental health treatment, victimization, and illegal activities measures. Adolescents in the CHS cohort were more likely to have longer lengths of stay and receive over three times as many hours of treatment. Mixed effects models revealed that CHS participants were significantly more likely to report a decrease in recovery environment risk, an increase in self-help attendance after treatment, and greater decreases in emotional problems, while CYT participants were significantly more likely to report decreases in their substance use. The results suggest that neither the best-practice nor the research-based interventions were clearly superior and call for a more rigorous randomized field experiment to better understand the differences in effectiveness between interventions.

Recently, we have developed collagen crosslinking induced by combined riboflavin/UVA treatment, thus increasing the biomechanical rigidity of the cornea to treat progressive keratoconus. The present safety study was performed to evaluate possible cytotoxic effects of combined riboflavin/UVA treatment on the corneal endothelium in vitro. Endothelial cell cultures from porcine corneas were treated with 500 microM riboflavin solution, exposed to various endothelial UVA irradiances (370 nm) ranging from 0.1 to 1.6 mW/cm2 for 30 min and evaluated 24 h later using trypan blue staining and Yopro fluorescence staining. The effect of either treatment alone (UVA irradiation ranging from 0.2 to 6 mW/cm2) was also tested. An abrupt cytotoxic threshold irradiance level was found at 0.35 mW/cm2 after combined treatment with riboflavin plus UVA irradiation and at 4 mW/cm2 with UVA irradiation alone. Riboflavin alone was not toxic. A cytotoxic effect of the combined riboflavin/UVA treatment on corneal endothelial cells is to be expected with a corneal thickness of less than 400 microm. Therefore, pachymetry should be routinely performed before riboflavin/UVA treatment to exclude patients at risk., (Copyright 2003 S. Karger AG, Basel)

The majority of people presenting for publicly-funded substance abuse treatment relapse and receive multiple episodes of care before achieving long-term recovery. This Early Re-Intervention experiment evaluates the impact of a Recovery Management Checkup (RMC) protocol that includes quarterly recovery management checkups (assessments, motivational interviewing, and linkage to treatment re-entry). Data are from 448 adults who were randomly assigned to either RMC or an attention (assessment only) control group. Participants were 59% female, 85% African American, and 75% aged 30-49. Participants assigned to RMC were significantly more likely than those in the control group to return to treatment, to return to treatment sooner, and to spend more subsequent days in treatment; they were significantly less likely to be in need of additional treatment at 24 months. This demonstrates the importance of post-discharge recovery management checkups as a means to improve the long-term outcomes of people with chronic substance use disorders.

A real-time quantitative TaqMan-PCR was established for the absolute quantification of extramatrical hyphal biomass of the ectomycorrhizal fungus Piloderma croceum in pure cultures as well as in rhizotron samples with non-sterile peat substrate. After cloning and sequencing of internal transcribed spacer (ITS) sequences ITS1/ITS2 and the 5.8S rRNA gene from several fungi, including Tomentellopsis submollis, Paxillus involutus, and Cortinarius obtusus, species-specific primers and a dual-labelled fluorogenic probe were designed for Piloderma croceum. The dynamic range of the TaqMan assay spans seven orders of magnitude, producing an online-detectable fluorescence signal during the cycling run that is directly related to the starting number of ITS copies present. To test the confidence of the PCR-based quantification results, the hyphal length of Piloderma croceum was counted under the microscope to determine the recovery from two defined but different amounts of agar-cultivated mycelia. Inspection of the registered Ct values (defined as that cycle number at which a statistically significant increase in the reporter fluorescence can first be detected) in a 10-fold dilution series of template DNA represents a suitable and stringent quality control standard for exclusion of false PCR-based quantification results. The fast real-time PCR approach enables high throughput of samples, making this method well suited for quantitative analysis of ectomycorrhizal fungi in communities of natural and artificial ecosystems, so long as applicable DNA extraction protocols exist for different types of soil.

Purpose: Previous clinical studies have suggested a positive effect of low-frequency pulsed electromagnetic fields (PEMF) on wound healing and inflammation in the eye. We tried to test the value of PEMF treatment in a hyphema animal model with well-defined conditions., Methods: After injection of citrated autologous blood for the production of hyphema, 16 rabbit eyes were treated with 10 or 20 mT for 60 min on 4 days within the postoperative week. Two control groups with hyphema alone (n = 8) and PEMF irradiation without hyphema (n = 4) were also included. The rate of resorption was recorded daily. Histopathologic evaluation was performed., Results: The incidence of endothelial cell damage and fibrotic clots was markedly reduced in the 10-mT group while the resorption time of 8 days was identical with the control group. In the 20-mT group, the complication rate and the resorption time was increased versus the control group., Conclusions: The use of PEMF treatment is of some, however, limited value as it did not reduce the resorption time of hyphema but displayed a dose-dependent, beneficial influence on some serious side effects. Future clinical studies with low-dose PEMF irradiation are justified and should determine the optimal dosage and suitable indications of PEMFs as an adjunctive treatment in ocular inflammation or trauma., (Copyright 2003 S. Karger AG, Basel)

Aims: Risk factors among adolescent substance abusers have been shown to correlate with substance use severity. Characteristics related to severity, such as demographic and family factors, peer influences, psychiatric co-morbidity and HIV risk behaviors, are examined for a sample of adolescent cannabis users entering treatment., Design: These data are from a clinical trial study utilizing blocked random assignment of clients to one of five treatment conditions. The study targeted adolescents entering outpatient treatment for primarily cannabis abuse or dependence., Setting: Treatment and research facilities in four metropolitan areas of the US were used to recruit study participants. Treatment was delivered in outpatient drug-free settings., Participants: Participants were 600 clients, ages 12-18, admitted to outpatient substance abuse treatment programs for cannabis problems, 96% with DSM-IV diagnoses of substance abuse or dependence, with the remaining 4% having at least one symptom of dependence plus significant problems indicating need for treatment., Measurements: The Global Appraisal of Individual Needs (GAIN) was used to collect the information presented in this paper. The GAIN incorporates DSM-IV criteria for substance use disorders, conduct disorder and attention deficit hyperactivity disorder, as well as dimensional (scale) measures for physical and mental health., Findings: All participants reported at least one symptom of substance use disorders, and 46% met the DSM-IV criteria for substance dependence, while 50% met criteria for a diagnosis of abuse. Only 20% of the participants perceived any need for help with problems associated with their drug or alcohol use. Clients participating in the study typically presented multiple problems at treatment entry, most often including conduct disorder, attention deficit hyperactivity disorder (ADHD), internal (mental) distress, and physical health distress. The co-occurrence of conduct disorder and ADHD was found in 30% of the sample. Clients meeting criteria for substance dependence tended to have more co-occurring problems and significantly less denial at admission., Conclusions: The characteristics of this sample exemplify the complex nature of adolescent substance use and abuse among adolescents entering outpatient treatment programs. Patterns of co-occurring problems are at rates comparable to those found in other clinical studies. Those with more severe substance use disorders tend to manifest more problems of social functioning, more mental health problems, and physical health problems. Implications of these findings are discussed in terms of treatment needs, challenges, and prognostic implications.

In many treatment systems, adolescents referred to residential treatment have the most serious alcohol or other substance use disorders and are at high risk of relapse. Upon discharge, these adolescents are typically referred to continuing care services, however, linkage to these services is often problematic. In this study, 114 adolescents (76% male) who stayed at least 7 days in residential treatment were randomly assigned to receive either usual continuing care (UCC) or UCC plus an assertive continuing care protocol (ACC) involving case management and the adolescent community reinforcement approach. ACC participants were significantly more likely to initiate and receive more continuing care services, to be abstinent from marijuana at 3 months postdischarge, and to reduce their 3-month postdischarge days of alcohol use. Preliminary findings demonstrate an ACC approach designed for adolescents can increase linkage and retention in continuing care and improve short-term substance use outcomes.

We have recently shown the CD44 variant isoform 10 (CD44v10) to be expressed on reactive as well as malignant cutaneous lymphocytes; however, the functional consequences of CD44v10 expression on lymphocytes are not elucidated. By using appropriately transfected lymphatic cells we analyzed the role of CD44v10 on lymphocytes in cell-matrix adhesion and homotypic and heterotypic cell-cell adhesion assays. Despite a low binding affinity to hyaluronan, CD44v10-expressing lymphocytes exhibited heterotypic cell-cell adhesion to inflamed dermal microvascular endothelium and keratinocytes, as indicated by Stamper-Woodruff assays on tissue sections of delayed type hypersensitivity reactions and adhesion assays with cultured keratinocytes and cytokine-stimulated human dermal microvascular endothelial cells. Antibody-blocking assays excluded interaction of CD44v10 with the principal CD44 ligand hyaluronan as well as involvement of selectins or integrins in these heterotypic cell-cell adhesion assays. In contrast, cellular aggregation assays with fluorescence-labeled CD44v10- and CD44H-expressing lymphocytes revealed homotypic CD44v10/CD44v10 binding as well as binding of CD44v10 with CD44H. Heterotypic cell-cell adhesion assays with ultraviolet-A-irradiated CD44v-negative cytokine-stimulated endothelial cells demonstrated binding kinetics of CD44v10-expressing lymphocytes paralleling those of endothelial CD44H expression. These results imply that a hyaluronan-independent CD44v10/CD44H-mediated pathway is involved in lymphocyte infiltration into the dermis and epidermis of inflamed skin and suggest modulation of CD44H expression on inflamed dermal microvascular endothelium as a mechanism of ultraviolet-A-induced therapeutic effects on the skin.

Interactions between infiltrating T cells and keratinocytes via the secretion of the TH1 cytokines interleukin (IL) 2 and interferon gamma (INF-gamma), the keratinocyte growth factor transforming growth factor alpha (TGF-alpha) and the cytokines IL-6 and IL-8 are thought to be the predominant mechanisms inducing skin lesions in psoriatic patients. Systemic treatment of psoriasis with fumaric acid derivatives (FAEs) has been reported to be effective in the treatment of psoriasis, but the mode of action is still unknown. To clarify this phenomenon, keratinocytes from psoriatic patients as well as from healthy volunteers were mono- and cocultured with HUT 78 T cells with/without the addition of FAEs; the cytokine concentrations were then measured in the culture supernatants. Furthermore, mRNA expression was determined in epidermal growth factor (EGF) -activated keratinocytes as well as in phytohaemagglutinin (PHA)-activated HUT 78 T cells. Only dimethylfumarate (DMF) diminished IL-6 and TGF-alpha secretion in the psoriatic cocultures. However, it did not have this effect on cocultures from control subjects or on monocultures. DMF suppresses EGF-induced TGF-alpha mRNA induction in psoriatic keratinocytes. DMF inhibited INF-gamma secretion in all cultures but stimulated the IL-10 secretion. This immunomodulation away from the TH1 cytokine IFN-gamma to the TH2 cytokine IL-10 was confirmed in HUT 78 T cells by Northern blot analysis. An increased number of eosinophils is a known side-effect in patients treated with this drug, suggesting a clinical relevance of this immunomodulation in vivo. This immunomodulation and the suppression of cytokines from the psoriatic cytokine network could be responsible for the beneficial effect of DMF in the treatment of a hyperproliferative and TH1 cytokine-mediated skin disease.

The remarkable functional diversity of the cell surface receptor CD44 may be due to expression of multiple variant isoforms generated by alternative splicing of variant exons. Functional and correlative data implicate a role of CD44 variant isoforms in adhesion dependent processes such as lymphocyte recirculation and tumor progression and metastasis. We have analyzed 25 primary cutaneous lymphomas and 35 reactive lymphoid cell skin infiltrates or T cell-mediated skin diseases for the expression of CD44 variant isoforms. Irrespective of histologic typing, staging, and grading, cutaneous lymphomas as well as nonmalignant skin-infiltrating CD3+ CD4+ and CD8+ T and CD19+ B lymphocytes exhibited a strong expression of CD44v10 and a moderate expression of CD44v3 as determined by immunohistochemistry, immunofluorescence microscopy, and mRNA analysis. Expression of v5, v6, v7, and v9-containing CD44 variant isoforms was not detected. Furthermore, flow cytometry revealed expression of CD44v10 on a significant proportion of peripheral blood lymphocytes from Sézary's syndrome patients and a remarkable co-expression with cutaneous lymphocyte antigen. These results indicate a distinct CD44 variant isoform expression pattern associated with skin-homing lymphocytes different to lymphatic cells at noncutaneous sites. This differential expression pattern of CD44 variant isoforms may contribute to the development of lymphocyte skin infiltrates and/or the unique biologic behavior of cutaneous lymphomas.

Evidence suggests an association between alcohol consumption and psoriasis. This relationship is still undefined, although long-term alcohol intake influences the immune system. Interactions between T cells and keratinocytes are important for the pathogenesis of psoriasis, by secretion of pro-inflammatory cytokines and growth factors in psoriatic skin. IL-2, IL-6, IL-8, IFN-gamma and TGF-alpha are hallmark cytokines in a psoriatic cytokine network. We investigated whether ethanol influences the secretion of these cytokines using a co-culture model with keratinocytes from psoriatic patients (n = 9) or from healthy controls (n = 9), with HUT 78 lymphocytes, and determined the cytokine levels with or without ethanol treatment in the culture supernatants. TGF-alpha and IFN-gamma levels were elevated in the ethanol-treated psoriatic co-cultures, to 150% and 175% respectively, but neither in co-cultures with keratinocytes derived from healthy control individuals nor in monocultures. Treatment with ethanol elevated slightly the IL-6 levels in the monocultures from psoriatic and control keratinocytes to 125% but not in HUT 78 monocultures. In the psoriatic co-cultures, IL-6 levels were elevated in the culture supernatants to almost 160%, but they were not influenced by ethanol in co-cultures with control keratinocytes. The cytokine levels of IL-8 or IL-2 were not significantly influenced in the psoriatic mono- and co-cultures or in HUT 78 cultures. If ethanol influences the cytokine secretion of psoriatic keratinocytes and HUT 78 lymphocytes in co-culture conditions, these data suggest that ethanol could also influence the psoriatic cytokine network in vivo, which may explain the explain the aggravation of this disease in alcohol-consuming psoriatic patients.

The predominant cutaneous side effect of lithium is the exacerbation or aggravation of psoriasis, but the pathogenesis is still unclear. The hyperproliferation of keratinocytes and a dense lesional infiltrate of mononuclear cells are the hallmarks of psoriatic skin lesions. Interactions between keratinocytes and T cells are thought to be one reason for an increased secretion of proinflammatory cytokines and growth factors. To investigate whether lithium influences cytokines of the "psoriatic cytokine network', we established a coculture model with keratinocytes from psoriatic patients and from healthy controls cultured with HUT 78 lymphocytes and measured the cytokine levels of Il-2, Il-6, Il-8, IFN gamma and TGF alpha in the culture supernatants after treatment with lithium. Il-6 levels were slightly elevated in the supernatants obtained from psoriatic and control keratinocyte cultures after lithium treatment, but IFN gamma and Il-2 levels were elevated only in the lithium-treated cocultures with psoriatic keratinocytes. In contrast, these two cytokines were not affected by lithium in HUT 78 monocultures or in cocultures with normal epidermal cells. We also found slightly elevated TGF alpha levels in lithium-treated psoriatic cocultures but not in control cultures. We therefore demonstrated that lithium influences the cell communication of psoriatic keratinocytes with HUT 78 lymphocytes by triggering the secretion of TGF alpha, Il-2 and, massively, IFN gamma. It seems possible that lithium also influences similar parts of the psoriatic cytokine network in vivo.

Endothelial cell (EC) activation plays a key role in the inflammatory response by promoting the margination of leukocytes in inflamed loci. Augmented leukocyte margination to activated EC is mediated by the increased display of leukocyte adhesion molecules on EC surface membranes. The biocompatibility of synthetic oxygen-transport fluids is intimately linked to EC function, since one of the first tissues encountered by such fluids is the vascular endothelium. We investigated the effect of one such agent, a phospholipid-based perfluorocarbon emulsion containing 90% w/v perfluorooctyl bromide (perflubron, PFOB) on EC activation. Human umbilical vein EC (HUVEC) were activated by 5 U/ml interleukin-1 (IL-1), 20 U/ml tumor necrosis factor (TNF), or 50 ng/ml E coli endotoxin (LPS) in the presence or absence of up to 20%, w/v perflubron. HUVEC activation was monitored by the extent of up-regulation of expression of intercellular adhesion molecule-1 (ICAM) and endothelial-leukocyte adhesion molecule-1 (ELAM). Exposure of HUVEC to perflubron did not alter the upregulation of ICAM or ELAM in response to IL-1 or TNF (n = 20). However, at 10% perflubron ICAM upregulation in response to LPS was inhibited by 95 +/- 6% (n = 9; p < .05). ELAM expression was similarly affected. The concentration of perflubron required to diminish LPS-induced up-regulation by 50% was 6.0 +/- 0.6% (n = 3). The inhibitory effect of 10% perflubron was overcome by > 1 microgram/ml LPS (n = 3) and the inhibitory effect was attenuated by adding perflubron to the cultures after LPS. In agreement with the above, additional experiments showed that incubation of LPS with perflubron prevented LPS-induced stimulation of TNF synthesis by a murine macrophage (RAW) cell line (n = 3). We conclude: 1) perflubron neither activates HUVEC nor interferes with HUVEC activation by IL-1 or TNF, 2) perflubron prevented HUVEC activation by LPS in a dose and time-dependent manner, 3) perflubron prevented LPS-induced activation of more than one cell line. Taken together, the data suggest that perflubron may bind and sequester limited concentrations of LPS. Whether this property of perflubron also occurs upon in vivo infusion and whether it might be clinically useful in preventing some of the adverse effects of endotoxemia are unknown.

Endothelial cell (EC) activation plays a key role in the inflammatory response by promoting the margination of leukocytes in inflamed loci. Augmented leukocyte margination to activated EC is mediated by the increased display of leukocyte adhesion molecules on EC surface membranes. The biocompatibility of synthetic oxygen-transport fluids is intimately linked to EC function, since one of the first tissues encountered by such fluids is the vascular endothelium. We investigated the effect of one such agent, a phospholipid-based perfluorocarbon emulsion containing 90% w/v perflurooctyl bromide (perflubron, PFOB) on EC activation. Human umbilical vein EC (HUVEC) were activated by 5 U/ml interleukin-1 (IL-1), 20 U/ml tumor necrosis factor (TNF), or 50 ng/ml E coli endotoxin (LPS) in the presence or absence of up to 20%, w/v perflubron. HUVEC activation was monitored by the extent of up-regulation of expression of intercellular adhesion molecule-1 (ICAM) and endothelial-leukocyte adhesion molecule-1 (ELAM). Exposure of HUVEC to perflubron did not alter the up-regulation of ICAM or ELAM in response to IL-1 or TNF (n = 20). However, at 10% perflubron ICAM up-regulation in response to LPS was inhibited by 95 +/- 6% (n = 9; p less than .05). ELAM expression was similarly affected. The concentration of perflubron required to diminish LPS-induced up-regulation by 50% was 6.0 +/- 0.6% (n = 3). The inhibitory effect of 10% perflubron was overcome by greater than 1 ug/ml LPS (n = 3) and the inhibitory effect was attenuated by adding perflubron to the cultures after LPS.(ABSTRACT TRUNCATED AT 250 WORDS)

The ultrastructure of the ciliary process vasculature in cynomolgus monkeys is described with transmission electron microscopy. Special attention is paid to a special segment of the anterior arterioles (afferent segment) and to the end of the marginal venule (efferent segment)-vascular structures which have been described as haemodynamically important. The major arterial circle of iris (MACI), the exclusive blood supply of the ciliary processes, has only a one- or two-layered medium. A short distance after the anterior arterioles of the ciliary processes have branched off, these arterioles develop a characteristic segment of about 100 microns in length and which possesses a two-layered medium where prominent special myocytes lie on the adventitial side (afferent segment). Nerve endings with dense-core and large vesicles are closely associated to the vessel wall of these afferent segments. On the 'venous' side of the ciliary process vasculature, the very thin wall of the marginal ciliary process vessel becomes reinforced by a layer of myocytes in a segment which is located in the zone where the marginal vessel bends into the layer of the pars plana venules (efferent segment). Here, the endothelium is substantially thickened and filled with different-sized granules. Nerve endings with clear- and large dense-core vesicles lie around this segment.

After splenectomy due to blunt abdominal trauma, splenectomized children showed a restricted pattern of T-cell immunodeficiency compared to age and sex-matched normal children. Peripheral blood total (CD3) T-cell counts of 11 splenectomized children of 43%, double positive helper (CD4) inducer subpopulation (CD29) cell counts of nine splenectomized children of 7%, and phytohemagglutinin (PHA)-induced T-cell proliferation of 11 splenectomized children of 53,206 c.p.m. were significantly (p less than 0.05) lower than values of normal children (61% CD3 cells, n = 12; 13% CD4CD29 cells, n = 11; 107,832 c.p.m. PHA-induced proliferation, n = 12). The deficit of CD4CD29 cell numbers may be due to impaired maturation of these particular CD4 lymphocytes and may explain diminished PHA-induced proliferation in small children. The significantly higher B-lymphocyte counts of splenectomized children (21%, n = 11; 558 cells/mm3, n = 10) compared with 12 normal children (14%; 329 cells/mm3) may be due to loss of the reservoir function of the spleen.

Intracapillary haemoglobin oxygenation (oxygen saturation) and haemoglobin concentration (corresponding with blood volume) were measured in different regions of the albino rabbit anterior eye segment using the Erlangen micro-lightguide spectrophotometer (EMPHO I). The tip of the microlightguide (active diameter 210 microns, cover diameter 0.5 mm) was placed in the vitreous by a goniometric mounting and controlled by a micromanipulator. After stepwise elevation of intraocular pressure (IOP) the haemoglobin oxygenation decreased slightly in the iris at an IOP-level of 60 mmHg, whereas in the three regions of the ciliary processes and in the peripheral choroid haemoglobin oxygenation did not decrease until values of 80 mmHg were applied. In contrast, haemoglobin concentration decreases when the IOP increases in all regions except in the pars plana where the haemoglobin concentration increased at 40 and 60 mmHg. The most pronounced reactive hyperaemia was found in the major ciliary processes. Quite passive changes of haemoglobin concentration were seen in the peripheral choroid. Effective regulatory mechanisms must exist which result in IOP-independent (20-60 mmHg) haemoglobin oxygenation, whereas pronounced changes in intracapillary haemoglobin concentration were observed. The decay of both parameters at IOP 80 mmHg is indicative of an exhaustion of their regulatory capacity. Epinephrine topically applied onto the conjunctival sac or injected into the common carotid artery led to a short-term decrease of haemoglobin concentration and, later, a hyperaemic response. A short-term haemoglobin deoxygenation was found especially in the major ciliary processes.

The architecture of the vasculature of the human anterior eye segment was studied by scanning electron microscopy of vascular resin casts. Regarding the major vessels it was found that the perforating branches of the anterior ciliary arteries (ACA) form an anastomozing circle which lies in the posterior portion of the ciliary muscle (intramuscular circle). The ACAs supply the outer and posterior parts of the ciliary muscle, partly the iris, and the peripheral choroid by recurrent ACA branches. The major arterial circle of iris (MACI) which lies more anteriorly is formed mainly by the long posterior ciliary arteries and supplies the inner and anterior portion of the ciliary muscle, the iris and the ciliary processes. The ciliary process vasculature consists of three different vascular territories with discrete arterioles and venules. The first vascular territory which is located at the anterior end of the major processes, is drained posteriorly by venules which pass the ciliary body without greater connections to the venules of the major ciliary processes. The second and third territories comprise the vasculature of the major and minor ciliary processes drained posteriorly by venules which are located at the margin of the ciliary processes. In supravital experiments with human autopsy eyes, a characteristic segment of arterioles supplying the first and second territory was found to be constricted after immersion with epinephrine in a similar way as in cynomolgus monkeys in vivo. Although the general arrangement of the ciliary process vessels is similar to that of the cynomolgus monkey, there are characteristic differences in the size of the territories and in the pattern of the capillary networks. The division of the ciliary process vasculature into three vascular territories may reflect a functional differentiation in the process of aqueous humour production.

Using scanning electron microscopy of vascular resin casts, it was found that the capillary network of the iridial ciliary processes is supplied by arterioles of its own and drained posteriorly by long isolated venules. These venules pass the ciliary body without greater connection to the venules of the major ciliary processes (shunt-system). Transmission electron microscopy showed that in contrast to the pigment epithelium (PE) of the major ciliary processes, the PE of the iridial processes develops elongated finger-like cytoplasmic processes which protrude into the stroma, often in the direction of the vessels, forming a 'basolateral labyrinth', like the kidney tubule epithelium. After paracentesis, an enlargement and leakage of the iridial ciliary process capillaries was found, resulting in resin leakage at various sites; no leakage was found in the vasculature of the major ciliary processes. Electron microscopically, the basolateral labyrinth of the PE appeared enormously enlarged, forming wide protein-containing intercellular spaces. These findings suggest that the function of the iridial ciliary processes in rabbits has a dual nature. Under normal circumstances, the main function of the iridial processes may be fluid reabsorption rather than aqueous humor secretion. In cases of paracentesis, for example, the very sensitive blood aqueous barrier of this area breaks down with resulting protein exudation.

The spontaneously hypertensive rats (SHR) show a lower intraocular pressure--despite high arterial blood pressure--than the normotensive Wistar Kyoto rats (NR). In SHR the quantitative evaluation of resin casts and flat-mount preparations of the blood vessels of the ciliary body and choroid showed a significant dilation of the vessels when compared to NR. In the capillaries of the ciliary processes, as well as in the choriocapillaries, a vascular rarefaction was seen. In all regions of the ciliary body the number of fenestrations found in the endothelium of the capillaries was reduced by about half in SHR. In addition, hyalinization of the connective tissue--particularly around the vessels at the base of ciliary processes--was seen in SHR. The morphological changes of the vasculature and connective tissue described here may be considered the cause of the reduced aqueous formation and low intraocular pressure found in SHR.

Tests are still lacking about the suitability of scanning electron microscopy (SEM) of vascular resin casts to show different functional states of peripheral blood vessels. With the aid of a vitalmicroscopic device, we tried to elaborate a vascular casting method using the model of the albino rat iris vasculature. Functional variations of the vasculature were induced by local application of epinephrine to one eye using the untreated fellow eye as a control. It was found that if our modification of Araldite plastic is injected via a systemic access and without preceding rinsing with fixatives or salt solutions there is a good correlation between the vessel diameters seen in SEM of resin casts and the vessel diameters found in the vitalmicroscopic observations. Thus, this method appears also suitable for studying the effect of vasoactive substances.

Architecture and functional reactions of the blood vessels of the rabbit ciliary processes were studied after administration of epinephrine and isoproterenol. A new corrosion cast technique was applied which allows the analysis of different functional stages in the vascular system by scanning electron microscopy. The ciliary process vasculature is divided into three different vascular territories, each supplied by individual arterioles: (1) the iridial ciliary processes; (2) the anterior (pre-lenticular) portion of the major ciliary processes; and (3) the minor ciliary processes localized post-lenticularly between the major processes. The three vascular territories differ not only in form and architecture of the capillaries but also in their reactions on vasoactive agents. After epinephrine, the earliest reactions were seen in the first vascular territory followed by the second, the third vascular territory being least sensitive. The most intense vasoconstrictory changes were found in the terminal arterioles which supply each vascular territory separately. This afferent vascular segment might therefore be considered to be the most important structure for regulation of blood flow through the ciliary processes.

Endotoxin-stimulated NBT-tests were carried out in 15 patients with hypocalcemia of varying etiology and in 14 normocalcemic children free of infection. In the control group the formazan cell percentage (FCP) was 73.8 +/- 1.6% (range 63% to 83%). In 5 patients with hypoparathyroidism or pseudohypoparathyroidism the FCP before treatment was lower than normal. Vitamin D3 therapy produced a rapid increase of serum calcium but normalisation of NBT-test was only achieved after a latent period of one or more months. Patients with hypocalcemic rickets and children with an acute relapse of the nephrotic syndrome also showed abnormal results. The clinical significance of the NBT-test in hypocalcemic conditions is discussed.

In the ciliary processes of the cynomolgus monkey three vascular territories with discrete arterioles and venules were found by means of scanning electron micrographs of vascular resin casts. The first vascular territory, which is located at the anterior end of the major processes, is drained posteriorly by long isolated venules, which pass the ciliary body without greater connections to the venules of the major ciliary processes, whereas the second and third territories comprise the vasculature of the major and minor ciliary processes drained posteriorly by veins which are located at the internal edge of the ciliary processes. With the functional resin casting method it could be demonstrated that 15 min after application of 20 micrograms of epinephrine into the conjunctival sac the terminal arterioles supplying the first vascular territory constricted most intensely, whereas the terminal arterioles related to the middle and posterior vascular territory of the ciliary processes constricted to a lesser extent. Twenty-five minutes after topical application of epinephrine only the posterior vascular territory and the capillaries of the ciliary muscle appeared filled in the resin casts. The vasculature of the anterior territories remained empty because of strong vasoconstriction of the supplying arterioles. The three morphologically different vascular territories with their different sensitivities to epinephrine may reflect a functional differentiation in respect to aqueous humour formation and resorption.

Several studies have demonstrated in the past that endogenous opioid peptides and opioid receptors may be involved as mediators of brain tissue growth and function in the neonate. Applying histological and autoradiographic methods, we have examined the effect of the mu-receptor-specific antagonist, naltrexone, on the proliferation of the 4-12-week-old rat forebrain subependymal layer. We found that naltrexone, when given daily throughout the weaning period, evoked a long-lasting increase of the mitotic rate and the [3H]thymidine labelling index. This effect was most significant about 8-10 weeks after ending the naltrexone treatment. Although a direct influence of naltrexone on long-term subependymal cell proliferation cannot be excluded, we are discussing evidence of an indirect effect via suppression of noradrenergic activity in the forebrain.

By means of pO2-needle electrodes the oxygen tension in the anterior chamber of rabbit and cynomolgus monkey eyes was measured and correlated with the topography. It can be clearly shown that the pO2 in front of the pupil is substantially lower than in front of the anterior iris surface. It is evident that the O2-supply of the anterior chamber is provided by the iris vasculature. This result was confirmed by measurements after partial or total iridectomy. A brief recapitulation of the morphology of the iris showed that the abundance of iris vasculature is well understandable in view of these pO2 measurements.

In albino rats of four age groups (male and female; 1, 6, 12 and 36 months) telogen hairs of the back were investigated in scanning electron microscopy at defined locations. The length of the cuticular 'scales' as well as the thickness of the hair shaft decreased significantly in the 36 month group of both sexes. In addition the scales of this group had irregular contours, cracks and spindle shaped inclusions.

In albino rabbits, the reactions of a defined venous segment of the ciliary process vasculature to vasoactive agents were studied using our new technique of in vivo microendoscopy and using supravital specimens of the anterior eye. This segment is situated in the pars plana of the ciliary body and is the continuation of the venules at the inner edge of the minor and major ciliary processes which posteriorly drain the blood in the veins of the peripheral choroid. Three- to 4 min after administration of carbachol, a constriction of this efferent venous segment was seen in the in vivo microendoscopy as well as in supravital specimens. The adjacent vessel segments remained relatively unchanged. Two- to 3 min after intra-arterial administration of atriopeptin (ANP), an intense constriction of the efferent venous segment, followed by a reactive hyperaemia, was found by in vivo microendoscopy. The iris veins which collect the blood from the iris and the iridial ciliary processes pass the pars plana without touching the ciliary process vasculature. No reactions to the vasoactive agents tested were observed in these vessels. It has been concluded that the efferent venous segment of the ciliary process may play a role in the regulation of perfusion pressure within the ciliary process capillaries.

Intraocular microendoscopy is introduced as a new method which allows a direct in vivo observation of the microvasculature of the eye. Using video equipment, a quantitative evaluation of changes in vessel diameters, e.g. after administration of vasoactive agents, and an estimation of blood oxygenation are possible. Experimental studies with fluorescent dyes can also be performed using special filters. In albino rabbits, no apparent vascular disturbances were observed under certain experimental conditions. Touching a ciliary process with the tip of the endoscope immediately resulted in a vasodilation and stoppage of blood flow, surprisingly in the affected area only. After epinephrine, the locally traumatized ciliary processes remained unchanged while the vessels of the neighboring ciliary processes constricted intensely. After reduction of the intraocular pressure the major ciliary processes began to swell. A leakage of fluorescein-dextran was only found in the iridial ciliary processes.

Stimulation of salt galnd secretion in domestic ducks in vivo increased the cyclic GMP concentration of the tissue, but had no effect on cyclic AMP levels. Methacholine, which is known to stimulate sodium transport by the glands both in vivo and in vitro, stimulated ouabain-sensitive respiration in salt gland slices. Cyclic GMP stimulated ouabain-sensitive respiration to the same extent as methacholine. Guanylate cyclase stimulators, hydroxylamine and sodium azide, also stimulated ouabain-sensitive respiration. The stimulation of ouabain-sensitive respiration by methacholine was blocked either by atropine or by removal of calcium from the incubation medium. The stimulation of ouabain-sensitive respiration by cyclic GMP still occurred in the absence of calcium. The above observations seem to indicate that cyclic GMP acts as a tertiary link in the process of stimulus-secretion coupling in the tissue.

Intraocular pressure (IOP) and arterial blood pressure (BP) were recorded manometrically in normotensive Wistar Kyoto rats (NR) and stroke-prone spontaneously hypertensive rats (SHR). IOP was significantly lower in SHR (7.8 +/- 0.2 mm Hg) compared to NR (15.9 +/- 0.4 mm Hg). In NR, administration of vasoactive substances (kallikrein, bradykinin, angiotensin I and II) or bloodletting resulted in significant IOP reactions, which ran nearly parallel to the acute BP changes. In SHR, however, IOP showed little reaction after comparable changes in BP. The cause of the low IOP in SHR is unknown. It is assumed that in SHR rarefaction of arterioles and capillaries and a decrease in the compliance of eye vessels, in combination with an increase in the distensibility of the bulbus at this low IOP level, contribute to the lack of IOP response after administration of vasoactive drugs.

The reactions of the ciliary-process microvasculature following administration of various vasoactive substances were studied in the albino rabbit using a new method of intraocular microendoscopy. This technique allows an in vivo observation of arterioles, capillaries and venules of the ciliary body and iris. As long as these tissues are not traumatized, the newly described method of intraocular microendoscopy produces no reactive changes in the vasculature. The video images of microendoscopy were also evaluated quantitatively. Administration of substance P caused a short-term ischemic phase in the ciliary-process vasculature which preceded a long-term hyperaemia. After topical administration of epinephrine as well as intra-arterial administration of epinephrine, phenylephrine and isoproterenol, rapid and intense vasoconstrictory or vasodilatory reactions were seen in the terminal arterioles of the vascular territories in the ciliary processes. The terminal arterioles of the iridial ciliary processes responded faster and more intensely than those of the major ciliary processes. It is concluded that the terminal arterioles play an important role in blood-flow regulation of the ciliary processes and function as special afferent vessel segments which control the circulation within the ciliary-process capillaries.