Maturation and refinement of the maculae and foveae in the Anolis sagrei lizard.

The fovea is a pit in the center of the macula, which is a region of the retina with a high concentration of photoreceptor cells, which accounts for a large degree of visual acuity in primates. The maturation of this primate visual acuity area is characterized by the shallowing and widening of the foveal pit, a decrease in the diameter of the rod-free zone, and an increase in photoreceptor cells packing after birth. Maturation occurs concurrently with progressing age, increasing eye size, and retinal length/area. These observations have led to the hypothesis that the maturation of the fovea might be a function of mechanical variables that remodel the retina. However, this has never been explored outside of primates. Here, we take advantage of the Anolis sagrei lizard, which has a bifoveated retina, to study maturation of the fovea and macula. Eyes were collected from male and female lizards-hatchling, 2-month, 4-month, 6-month, and adult. We found that Anolis maculae undergo a maturation process somewhat different than what has been observed in primates. Anole macular diameters actually increase in size and undergo minimal photoreceptor cell packing, possessing a near complete complement of these cells at the time of hatching. As the anole eye expands, foveal centers experience little change in overall retina cell density with most cell redistribution occurring at macular borders and peripheral retina areas. Gene editing technology has recently been developed in lizards; this study provides a baseline of normal retina maturation for future genetic manipulation studies in anoles.

Asymmetric band gap shift in electrically addressed blue phase photonic crystal fibers.

In this paper, we present electrooptic experiments on photonic crystal fibers filled with a liquid crystalline blue phase. These fibers guide light via photonic band gaps (PBGs). The blue phase is isotropic in the field-off state but becomes birefringent under an electric field. This leads to a polarization dependent shift of the PBGs. Interestingly, the effect on the PBGs is asymmetrical: while the short wavelength edges of the PBGs shift, the long wavelength edges are almost unaffected. By performing band gap and modal analyses via the finite element simulations, we find that the asymmetric shift is the result of the mixed polarization of the involved photonic bands. Finally, we use the band gap shifts to calculate effective Kerr constants of the blue phase.

[Novel immunodiagnostics for inflammatory arthritis]. / Neue Immundiagnostik bei Arthritiden.

Immunodiagnostics play an important role in the differential diagnostics of arthritis but the test results must be interpreted with respect to the clinical context. The detection of antibodies against citrullinated proteins has significantly improved the immunodiagnostics of arthritis, whereas the importance of testing for rheumatoid factor has decreased due to the low specificity. Antibodies against carbamylated or oxidized proteins will expand the immunodiagnostics of arthritis (especially rheumatoid arthritis) in the future. In contrast, the determination of cytokine concentrations in plasma or synovial fluid plays a subordinate role in the differential diagnostics of arthritis. Indirect immunofluorescence continues to be the gold standard in the detection of antinuclear antibodies (ANA) and in the case of positive results further testing for antigen specificity should be carried out. The presence of ANA is not necessarily associated with autoimmune diseases. An example of a non-pathogenic ANA is anti-DFS70 antibodies.

Liquid crystal assisted optical fibres.

Microstructured fibres which consist of a circular step index core and a liquid crystal inclusion running parallel to this core are investigated. The attenuation and electro-optic effects of light coupled into the core are measured. Coupled mode theory is used to study the interaction of core modes with the liquid crystal inclusion. The experimental and theoretical results show that these fibres can exhibit attenuation below 0.16 dB cm(-1) in off-resonant wavelength regions and still have significant electro-optic effects which can lead to a polarisation extinction of 6 dB cm(-1).

Corticotropin releasing hormone (CRH) response in patients with early rheumatoid arthritis due to polymorphisms in the CRH gene.

OBJECTIVES: To further evaluate the impact of corticotropin releasing hormone (CRH) promoter polymorphisms on the stress response in rheumatoid arthritis (RA) patients an insulin hypoglycaemia test (IHT) was performed studying the dynamics of CRH production. METHODS: Polymorphisms of the human CRH promoter were determined in controls and cortisol naive patients with early RA. Serum glucose and plasma CRH were measured at baseline and up to 120 min following induction of hypoglycemia. RESULTS: During IHT RA patients bearing the A2B2 allele exhibited an earlier CRH response compared to A1B1 positive patients. CONCLUSIONS: Stress-induced response of CRH is differentially modulated by CRH promoter polymorphisms in RA patients.

[Anemia in patients with rheumatoid arthritis]. / Anämie bei Patienten mit rheumatoider Arthritis.

One of the most frequent extra-articular organ manifestations in rheumatoid arthritis (RA) is anemia. As anemia in RA patients may result in severe symptoms and aggravation of other disease manifestations (e.g. arteriosclerosis), the influence on the course of RA is profound. However, the importance of anemia in RA patients is frequently underestimated. The etiology of anemia in RA is complex. Anemia of inflammation (AI) and iron deficiency anemia, alone or in combination are the most frequent forms of anemia in RA. Changes in iron metabolism are the leading causes of anemia in RA patients and mainly induced by the altered synthesis and function of hepcidin and ferroportin. Hepcidin, a peptide produced in the liver and immunocompetent cells, impairs the expression of ferroportin on iron-secreting cells, thus reducing iron bioavailability. The typical changes of iron metabolism and hepcidin synthesis in RA are induced by proinflammatory cytokines, primarily interleukin-6. Hence, the treatment of RA with cytokine antagonists has significant therapeutic implications on anemia in the context of inflammation and impaired iron metabolism.

[Bitemporal scalp necrosis : a very rare manifestation of giant cell arteritis]. / Bitemporale Skalpnekrose : Eine sehr seltene Manifestation der Riesenzellarteriitis.

A 71-year-old woman developed progressive spreading of bitemporal scalp necrosis within 4 weeks accompanied by headaches, myalgia of the shoulder girdle and muscle weakness that had started a few months previously. No additional diseases were reported. The suspected temporal giant cell arteritis could be confirmed by temporal artery biopsy. Therapy with glucocorticoids led to a rapid resolution of clinical symptoms and was tapered over 18 months. Recovery of the scalp necrosis emerged following second intention healing and split-skin transplantation of necrotic areas after successful wound conditioning. The case study demonstrates a rare and serious complication of temporal arteritis which is often accompanied by a poor prognosis.

Association between beta2 adrenergic receptor polymorphisms and rheumatoid arthritis in conjunction with human leukocyte antigen (HLA)-DRB1 shared epitope.

OBJECTIVE: In the present work, the frequency of inherited polymorphisms of the beta2 adrenergic receptor (beta2AR) gene and their association with rheumatoid arthritis (RA) as well as human leukocyte antigen (HLA)-DRB1 alleles was examined. METHODS: An allele-specific polymerase chain reaction was used to determine the common variants of the beta2AR at positions 16, 27 and 164 in patients with RA (n=310) and ethnically matched healthy controls (n=305) from Germany. HLA-DRB1 genotyping was performed by oligonucleotide hybridisation of enzymatically amplified DNA allowing low-resolution HLA-DRB1 genotyping comprising specificities DRB1*01 to DRB1*17. RESULTS: Arginine (Arg) at codon 16 was present in 278 patients with RA (89.7%) compared to 202 controls (66.2%; odds ratio (OR) 4.43, 95% CI 2.81 to 7.02, p<0.001). Homozygosity for Arg16 was found in 107 patients with RA (34.5%) compared to 14 controls (4.6%; OR 10.9, CI 5.9 to 20.5, p<0.001). Stratifying patients for their HLA-DR status revealed that homozygosity for Arg16 exhibited the greatest risk for RA in combination with HLA-DRB1*04 (OR 17.1, 95% CI 1.71 to 414.4, p=0.004). Interestingly, patients with the Arg16 allele have a younger mean (SD) age at disease onset compared to patients without Arg16 (46.1 (2.0) vs 53.1 (2.7) respectively, p<0.05). Furthermore, 93.3% patients with homozygosity for Arg16 were positive for anti-cyclic citrullinated peptide (CCP) antibodies vs 75% patients with homozygosity for Gly16 (p<0.05). CONCLUSION: There was a highly significant distortion between patients with RA and controls in the distribution of beta2AR polymorphisms at codon 16, contributing (together with the HLA-DR alleles) to the genetic background of RA.

Beta2-adrenergic receptors mediate the differential effects of catecholamines on cytokine production of PBMC.

We determined characteristics of beta2-adrenergic receptors (beta2R) on peripheral blood mononuclear cells (PBMC) and cytokine production after mitogenic stimulation and coincubation with catecholamines. PBMCs were stimulated with interleukin-2 (IL-2), tetanus toxoid (TT), anti-CD3 antibody, or phytohemagglutinin (PHA). The cytokines interferon-gamma (IFN-gamma), IL-4, and IL-6 were determined by ELISA following coincubation with high-dose (10(-5) M) and low-dose (10(-9) M) epinephrine (EPI) and norepinephrine (NE). Intracellular IFN-gamma and IL-4 were studied by FACS analysis. The beta2R density was investigated using a radioligand binding assay. The stimuli induced various cytokine profiles in PBMCs. Synthesis of IFN-gamma was induced by all mitogens and could be suppressed by catecholamines (26%-85% reduction). In PHA-stimulated PBMCs, IL-4 synthesis was decreased by high-dose catecholamines (24%-28% reduction). Adding a beta-blocking agent attenuated most catecholamine effects. A highly significant negative correlation between the density of beta2R with IFN-gamma and IL-6 levels of PHA-activated PBMCs (r = -0.88 to -0.96, p < 0.01-< 0.001) was observed. The results indicate that the density of beta2R on PBMC plays a role in mediating the differential catecholamine effects on cytokine production of PBMC. Furthermore, changes in cytokine expression induced by catecholamines favor Th2 responses.

Reduced catecholamine response of lymphocytes from patients with rheumatoid arthritis.

Catecholamines modulate lymphocyte function via stimulation of beta2-adrenergic receptors (beta2R). Previous investigations revealed a decreased density of beta2R on peripheral blood mononuclear cells (PBMC) in patients with chronic rheumatic diseases. Aim of the present study was to determine the impact of this decrease on catecholamine response of PBMC from patients with rheumatoid arthritis (RA) in vitro. PBMC from 17 patients with RA and 12 healthy blood donors (HD) were investigated. Beta2R were determined by a radioligand binding assay. The effects of epinephrine (E) and norepinephrine (NE) on PBMC proliferation were studied using cells activated with pokeweed mitogen (PWM) and monoclonal anti-CD3-antibodies (OKT3), respectively. In parallel, alpha1- or beta-receptor antagonist were added to the culture to determine the specificity of the catecholaminergic effects. The results showed that depending on the stimulus and the catecholamine concentration employed E and NE exert inhibitory (OKT3) or stimulatory signals (PWM) on lymphocyte proliferation. Inhibitory effects could be abolished by adding beta-antagonist, while stimulatory signals were diminished after addition of alpha1- of beta-antagonist. Patients with RA showed a significantly reduced density of beta2R compared to HD paralleled by a significantly reduced influence of catecholamines on lymphocyte function. The study demonstrates the intricate relationship between PBMC reactivity and catecholamine effects that are mediated via alpha1- and beta-adrenergic receptors. In this respect the reduced catecholamine response of PBMC from RA patients may contribute to the pathogenic process of RA.

Immunopathogenesis of rheumatic diseases in the context of neuroendocrine interactions.

Growing evidence supports the hypothesis that alterations of the stress response and interactions between the neuroendocrine and immune systems contribute to the pathogenesis of rheumatic diseases such as rheumatoid arthritis (RA). In particular, the hypothalamus-pituitary-adrenal (HPA) axis and the autonomic nervous system (ANS) are of special interest. Polymorphisms of the corticotropin-releasing hormone (CRH)-regulating region have been described recently. These polymorphisms are differentially distributed in RA patients and healthy subjects of various ethnic origin, thus supporting the hypothesis that they represent a new genetic marker for RA susceptibility. The decreased expression of beta(2)-adrenergic receptors (beta(2)-R) on lymphatic cells in rheumatic diseases like RA, together with an impaired influence of catecholamines on immune function in these patients, further underlines the concept of a dysfunction of the ANS in rheumatic diseases. Results from work in this field will provide more insight into the pathogenesis of RA and help to establish novel therapies for this chronic rheumatic disease.

Decreased catecholamine-induced cell death in B lymphocytes from patients with rheumatoid arthritis.

The expression of beta2-adrenergic receptors (beta2-R) on B lymphocytes and agonist-induced cAMP production is reduced in patients with rheumatoid arthritis (RA). To further study functional consequences of the diminished beta2-R density on B lymphocytes in RA patients, agonist-induced cell death was evaluated and compared to healthy controls. B lymphocytes from patients with RA and healthy controls were activated with anti-IgM-antibody. Coincubation was carried out with isoprenaline (iso, 0.001-10 microM). Apoptotic and necrotic cells were determined using Annexin-V and propidium-iodide staining. beta2-R-induced cell death in B cells from healthy volunteers was stimulated after 24 h (medium, 21.2 +/- 1.6%; iso, 34.6 +/- 4.4%; increase 59.3 +/- 10.1%). However, in RA patients the increase in cell death following beta2-R stimulation (21.8 +/- 8.9%) was significantly impaired (p = 0.02). Our data demonstrate that catecholamine-induced cell death after stimulation of beta2-R on B lymphocytes is decreased in RA patients, possibly contributing to the pathogenesis of the disease.

Disease activity related catecholamine response of lymphocytes from patients with rheumatoid arthritis.

In patients with chronic rheumatic diseases, a decreased density of beta 2-adrenergic receptors (beta 2R) on peripheral blood mononuclear cells (PBMC) could be demonstrated negatively correlating with various disease activity parameters. The aim of the present study was to determine the impact of this decrease on catecholamine response of PBMC from patients with rheumatoid arthritis (RA) in vitro. PBMC from 17 patients with RA and 6 healthy blood donors (HD) were investigated. The effects of epinephrine (E) and norepinephrine (NE) on PBMC proliferation were studied using cells activated with phytohemagglutinin (PHA) and monoclonal anti-CD3-antibodies (OKT3), respectively. The results revealed that lymphocytes of patients with RA showed a significantly reduced influence of catecholamines on PBMC function. In RA patients with high disease activity only, a shift to alpha 1-adrenergic-mediated catecholamine effects upon PBMC reactivity could be observed. The study demonstrates the intricate relationship between PBMC reactivity and catecholamine effects that is mediated via alpha- and beta-adrenergic receptors due to disease activity. In this respect the altered catecholamine response of PBMC from patients with RA may contribute to the pathogenic process of RA.

Comparison trial of four injectable anesthetics for laceration repair.

OBJECTIVES: To compare four injectable anesthetics (buffered 1% lidocaine, buffered 1% lidocaine with epinephrine, plain 1% lidocaine with epinephrine, and 0.5% diphenhydramine with epinephrine) for pain of infiltration and effectiveness of anesthesia during suturing of minor lacerations. METHODS: A prospective, randomized, double-blind, comparison trial of the above agents was performed in an urban ED; adults with simple linear lacerations without vascular compromise were enrolled. Physicians and patients ranked the pain of injection and suturing according to a 10-cm visual analog scale (VAS). Fisher's exact and Kruskal-Wallis tests were used to compare demographic data, and Kruskal-Wallis and Newman-Keuls tests were used in analysis of VAS rankings. The power of the study was 0.8 to detect a 1.4-cm difference in VAS readings, and 0.9 to detect a 1.7-cm difference. RESULTS: Seven of 200 enrolled patients were excluded due to improper data collection and 13 were removed from final statistical analysis due to need for additional anesthetic (treatment failures), leaving 180 subjects for final analysis. Demographic data were similar for the four groups (p > 0.05). Diphenhydramine with epinephrine was significantly more painful to inject than was buffered lidocaine or buffered lidocaine with epinephrine, according to both the patients (p = 0.0003) and the physicians (p = 0.0037). The two buffered compounds were slightly less painful to inject than was lidocaine with epinephrine, but statistical comparisons did not reach significance. For anesthesia effectiveness, lidocaine with epinephrine and buffered lidocaine with epinephrine were statistically better than buffered lidocaine or diphenhydramine with epinephrine (p = 0.0001 for the patients and the physicians). CONCLUSIONS: Buffered lidocaine with epinephrine and lidocaine with epinephrine were more effective anesthetics during suturing, according to both the physicians and the patients. There was a tendency toward less pain with infiltration in buffered solutions, compared with plain lidocaine with epinephrine, but the comparisons did not reach statistical significance. Diphenhydramine with epinephrine was more painful to inject than were buffered lidocaine with epinephrine and lidocaine with epinephrine, and was less effective anesthetically than the other three solutions.

[Rare cause of acute liver failure]. / Seltene Ursache eines akuten Leberversagens.

A rare cause of acute liver failure is adult onset Still's disease (AOSD), a systemic inflammatory disorder. We present the case of a 24-year-old woman who presented with acute liver failure necessitating high urgency liver transplantation. The diagnosis of AOSD was established in accordance with the Yamaguchi classification criteria, including arthralgia, fever, sore throat, rash and hepatosplenomegaly. The early detection and therapy of AOSD can possibly avoid the development of liver failure with a poor prognosis.

Promoter polymorphisms regulating corticotrophin-releasing hormone transcription in vitro.

To investigate whether polymorphisms in the corticotrophin-releasing hormone (CRH) promoter are associated with altered CRH gene regulation, we studied the reactivity of three recently described promoter variants in vitro. The 3625 bp variants A1B1, A2B1 and A2B2 of the human CRH promoter were cloned in the 5' region to a luciferase reporter gene and transiently transfected into both mouse anterior pituitary cells AtT-20D16vF2 and pheochromocytoma cells PC12. Incubation with 8-Br-cAMP alone or in combination with cytokines significantly enhanced the promoter activity in both cell lines studied by up to 22-fold. However, dexamethasone antagonised cAMP effects on CRH expression in AtT-20 cells while showing no effect on PC12 cells, indicating that tissue-specific factors play a crucial role. Among the haplotypes studied, A1B1 exhibited the greatest reactivity on various stimuli. Electric mobility shift assay (EMSA) was performed to study whether the described polymorphic nucleotide sequences in the 5' region of the hCRH gene interfere with binding of nuclear proteins. A specific DNA protein complex was detected at position -2353 bp for the wild type sequence only, possibly interfering with a binding site for the activating transcription factor 6 (ATF6). Taken together, this is the first study to demonstrate that CRH promoter reactivity varies between the compound promoter alleles.

Validation of the NOSGER (Nurses' Observation Scale for Geriatric Patients): reliability and validity of a caregiver rating instrument.

The Nurses' Observation Scale for Geriatric Patients (NOSGER) is a rating scale for use in geriatric patients that can be applied by nurses or other caregivers. It deals with the daily behavior of elderly patients and measures impairment in six areas (dimensions): memory; instrumental activities of daily living (IADL); (basic) activities of daily living (ADL); mood; social behavior; and disturbing behavior. Objectivity, stability, construct validity, and acceptance of the scale have been established in previous studies using an earlier version of the NOSGER. The present validation study considered 50 healthy old subjects, 25 patients with mild dementia, 25 patients with advanced (mostly moderate according to DSM-III-R criteria) dementia, and 25 elderly patients with depression. The NOSGER was completed by relatives in the case of subjects living in their own homes and by nurses or other caregivers for institutionalized subjects. In addition to the NOSGER, selected tests of concentration, memory, and performance were applied as outside criteria. Interrater reliability (objectivity) was estimated by variance component analysis. Values between rtt = .68 and rtt = .89 (all p < .001) were found for the six NOSGER dimensions, the values being higher for the cognitive dimensions (memory, IADL, ADL) than for the noncognitive ones (mood, social behavior, disturbing behavior). Retest reliability (stability), which was calculated via rank order correlations, was somewhat higher for the cognitive NOSGER dimensions (memory rs = .91, IADL rs = .92, ADL rs = .88; p < .001) than for the noncognitive ones (mood rs = .85, social behavior rs = .87, disturbing behavior rs = .84; p < .001). All these values satisfy the level of rtt > or = .80 required in accordance with psychometric standards. The concurrent validity of the NOSGER dimensions was assessed using correlations with external criteria with which similarity of content was expected. The NOSGER dimensions memory, IADL, ADL, and social behavior were found to correlate closely with external criteria of similar content, whereas no satisfactory concurrent validities were found for the dimensions mood or disturbing behavior. The NOSGER dimensions were also correlated with a number of unrelated external criteria so as to reveal any discordances. For the dimensions memory, IADL, ADL, and social behavior, no clear-cut discriminant validities were found. This suggests that these four dimensions may function as parameters not just of different areas of behavior, but also of a general factor that might be described as "cognitive intactness." As a further aspect of construct validity, significant differences (all p < .001) between the four groups of subjects were found in five of the six NOSGER dimensions (memory, IADL, ADL, mood, social behavior): The healthy subjects differed significantly from all three patient groups in five of the six dimensions; the moderately demented group differed from the depressed group in four of the six dimensions and from the mildly demented group in two of the six dimensions; and the mildly demented group differed significantly from the depressed group in terms of mood (significance levels are after application of the Bonferroni correction). Significant group differences (p generally < .001) were also found for most of the objective performance tests used (data not presented).