[Secondary polychondritis in Wegner's disease].
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Granulomatosis with Polyangiitis↗
Biomedical subjects
S Ullrich
Publications and source records attributed to S Ullrich.
Dynamics of photoinduced processes in adenine and thymine base pairs.
The excited-state dynamics of adenine and thymine dimers and the adenine-thymine base pair were investigated by femtosecond pump-probe ionization spectroscopy with excitation wavelengths of 250-272 nm. The base pairs showed a characteristic ultrafast decay of the initially excited pi pi* state to an n pi* state (lifetime tau(pi pi*) approximately 100 fs) followed by a slower decay of the latter with tau(n pi*) approximately 0.9 ps for (adenine)2, tau(n pi*) = 6-9 ps for (thymine)2, and tau(n pi*) approximately 2.4 ps for the adenine-thymine base pair. In the adenine dimer, a competing decay of the pi pi* state via the pi sigma* state greatly suppressed the n pi* state signals. Similarities of the excited-state decay parameters in the isolated bases and the base pairs suggest an intramonomer relaxation mechanism in the base pairs.
Adenine↗
Two-hour postdose concentration: a reliable marker for cyclosporine exposure in adolescents with stable renal transplants.
In pediatric renal transplant recipients, most patients receive maintenance treatment with cyclosporine (CsA) and mycophenolate mofetil (MMF). Until now, the 2-hour postdose CsA target level for combined maintenance treatment with MMF has not been defined. This prospective pilot study evaluated the pharmacokinetics of CsA under the influence of MMF to determine a reliable single CsA concentration time that correlates with the area under the curve (AUC(0-6h)) estimates for adolescents who were additionally treated with MMF during the late posttransplant period. The study included 13 adolescents (mean posttransplantation time, 3.5 +/- 2.55 years) with stable renal transplant function (S-Crea 121 +/- 40 micromol/L). CsA pharmacokinetic absorption profiles over a 6-hour dose interval (n = 26) were evaluated for the optimal single peak concentration using the CsA concentrations predose (C0) and at 1, 2, 3, 4, and 6 hours postdose (C1-6). Whereas C2 (mean 743.2 +/- 221.8 ng/mL) was the single point with the closest correlation to AUC(0-6h) (r2 = 0.86; P < .001), C0 (mean 120.5 +/- 35.2 ng/mL) showed the weakest correlation (r2 = 0.61, P = .002). C2 appears to be an accurate predictor of CsA exposure in adolescent kidney transplant recipients under maintenance immunosuppression in combination with MMF. Average values achieved with current dosing practices cluster around the target C2 ranges recommended for adults. The data provide a foundation for initiation of prospective clinical trials to assess the long-term risk for chronic allograft dysfunction among pediatric stable renal transplant patients in combination protocols.
Adolescent↗
A phase II trial of chimeric monoclonal antibody G250 for advanced renal cell carcinoma patients.
Chimeric monoclonal antibody G250 (WX-G250) binds to a cell surface antigen found on >90% of renal cell carcinoma (RCC). A multicentre phase II study was performed to evaluate the safety and efficacy of WX-G250 in metastatic RCC (mRCC) patients. In all, 36 patients with mRCC were included. WX-G250 was given weekly by intravenous infusion for 12 weeks. Patients with stable disease (SD) or response were eligible to receive additional treatment for 8 weeks. None of the 36 enrolled patients experienced any drug-related grade III or IV toxicity. Only three patients had grade II toxicity possibly related to the study medication. In all, 10 patients had SD and received extended treatment. One complete response and a significant regression was observed during the follow-up of the treatment. Five patients with progressive disease at study entry were stable for more than 6 months after study entry. The median survival after treatment start was 15 months. The weekly schedule of WX-G250 was well tolerated. With a median survival of 15 months after the start of this treatment and two late clinical responses, WX-G250 seems to be able to modulate mRCC. To improve the activity of WX-G250-specific antibody-dependent cellular cytotoxicity and the clinical response rate, currently combinations of WX-G250 with cytokines are in phase II trials.
Adult↗
[Categorical and dimensional assessment of "psychopathy" in German offenders. Prevalence, gender differences and age factors].
The personality construct "psychopathy" is of utmost importance in legal prognosis. In the last 20 years, a multitude of empirical research proved the predictive validity of this concept concerning the degree of dangerousness represented by an offender. In the present study, a representative, nonselected sample of 416 offenders was examined using the Screening Version of the Psychopathy Checklist (PCL:SV). The data were analysed both categorically and dimensionally according to the three-factor model proposed by Cooke and Michie. In comparison to North American Studies the prevalence of high scorers was significantly lower, implicating intercultural differences. Analyses of the effects of gender yielded higher scores on each of the three factors in male offenders. Concerning different age cohorts, it turned out that the arrogant and deceitful interpersonal style and deficient affective experience remained stable, whereas the impulsive and irresponsible behavioral style decreased with increasing age. Therefore, our results point out intercultural differences already shown in the prevalence of "psychopathy" and confirm the effects of gender and age concerning this construct.
Adult↗
A prospective open-label single-arm phase II study of chimeric monoclonal antibody cG250 in advanced renal cell carcinoma patients.
cG250 is an IgG1 kappa light-chain chimeric monoclonal antibody that binds to a cell surface antigen found on 95% of clear-cell renal cancer. A multicentre phase II study was performed to evaluate the safety and efficacy of repeated doses of cG250. Thirty-six patients with metastatic RCC were included. All patients were nephrectomized for the primary tumour. Twenty-one patients were pretreated (e.g. with IL-2, IFN-alpha). A weekly dose of 50 mg cG250 was given by i.v. infusion for 12 weeks. Patients with SD or tumour response (PR, CR) after 12 weeks of treatment could receive additional treatment for 8 more weeks. None of the 36 enrolled patients had any cG250 grade III or IV toxicity. Only three patients had grade II toxicity possibly related to the study medication. ELISA testing gave no evidence for relevant amounts of HACA. Eleven patients presented with SD and ten were eligible for extension treatment. After the end of the study in the follow-up period, one patient demonstrated a CR in week 38 and another patient with SD showed a significant reduction of the overall tumour load in week 44. Six additional patients with progressive disease at study entry were stable for more than six months after the treatment start. The weekly schedule of i.v. cG250 in patients with metastatic RCC was safe, very well tolerated and non-immunogenic in a 12-week treatment regimen. cG250 showed anti-tumour activity.
Adult↗
Membrane potential dependent modulations of calcium oscillations in insulin-secreting INS-1 cells.
This study was undertaken to examine the role of K(+) channels on cytosolic Ca(2+) ([Ca(2+)](i)) in insulin secreting cells. [Ca(2+)](i) was measured in single glucose-responsive INS-1 cells using the fluorescent Ca(2+) indicator Fura-2. Glucose, tolbutamide and forskolin elevated [Ca(2+)](i) and induced [Ca(2+)] oscillations. Whereas the glucose effect was delayed and observed in 60% and 93% of the cells, in a poorly and a highly glucose-responsive INS-1 cell clone, respectively, tolbutamide and forskolin increased [Ca(2+)](i) in all cells tested. In the latter clone, glucose induced [Ca(2+)](i) oscillations in 77% of the cells. In 16% of the cells a sustained rise of [Ca(2+)](i) was observed. The increase in [Ca(2+)](i) was reversed by verapamil, an L-type Ca(2+) channel inhibitor. Adrenaline decreased [Ca(2+)](i) in oscillating cells in the presence of low glucose and in cells stimulated by glucose alone or in combination with tolbutamide and forskolin. Adrenaline did not lower [Ca(2+)](i) in the presence of 30mM extracellular K(+), indicating that adrenaline does not exert a direct effect on Ca(2+) channels but increases K(+) channel activity. As for primary b-cells, [Ca(2+)](i) oscillations persisted in the presence of closed K(ATP) channels; these also persisted in the presence of thapsigargin, which blocks Ca(2+) uptake into Ca(2+) stores. In contrast, in voltage-clamped cells and in the presence of diazoxide (50mM), which hyperpolarizes the cells by opening K(ATP) channels, [Ca(2+)](i) oscillations were abolished. These results support the hypothesis that [Ca(2+)](i) oscillations depend on functional voltage-dependent Ca(2+) and K(+) channels and are interrupted by a hyperpolarization in insulin-secreting cells.
Adrenergic alpha-Agonists↗
A critical evaluation of commercial immunoassays for antineutrophil cytoplasmic antibodies directed against proteinase 3 and myeloperoxidase in Wegener's granulomatosis and microscopic polyangiitis.
OBJECTIVE: To evaluate the performance of 11 commercial enzyme-linked immunosorbent assay (ELISA) kits for the detection of antineutrophil cytoplasmic antibodies (ANCA) directed against proteinase 3 (PR3) and myeloperoxidase (MPO) in patients with Wegener's granulomatosis (WG) and microscopic polyangiitis (MPA). METHODS: Serum samples were taken from 92 patients with a histological and clinical diagnosis of WG (n=50) or MPA (n=42) and from 30 disease controls (systemic lupus erythematosus, n=15; rheumatoid arthritis, n=15) and 30 healthy controls. Each of the sera was tested for the presence of ANCA directed against PR3 and MPO using 11 commercially available direct ELISA kits, our in-house PR3- and MPO-ANCA capture ELISAs, and the indirect immunofluorescence technique (IFT). RESULTS: In tests for WG using PR3-ANCA, the commercial direct ELISA kits differed widely in their sensitivity (from 22 to 70%) and negative predictive value (NPV) (from 43 to 70%), but only moderately in their specificity (from 93 to 100%) and positive predictive value (PPV) (from 93 to 100%). The highest sensitivity (74%) and specificity (100%) for PR3-ANCA were obtained with the in-house capture ELISA. Similar differences and trends were noted for MPO-ANCA assays. Diagnostic sensitivity was more than 60% for four and at least 50% for six of the 11 ELISA kits. The PPV varied from 84 to 100% and the NPV from 58 to 70%. In tests for MPA, the MPO-ANCA ELISA kit designated F and the in-house capture ELISA were best (both had sensitivity 62% and specificity 100%). For both WG and MPA, maximum sensitivity for ANCA was obtained with IFT (80 and 70% respectively). CONCLUSION: Determination of PR3-ANCA and MPO-ANCA with the commercial direct ELISA kits achieved poor sensitivity for both WG and MPA. The in-house PR3 and MPO-ANCA capture ELISAs performed better than the commercial ELISAs, combining higher specificity with similar sensitivity. IFT remains the best method for ANCA detection in both diseases.
Adolescent↗
Macular hole size as a prognostic factor in macular hole surgery.
BACKGROUND/AIM: In 1991 there was a series of successful closures of a macular hole after vitrectomy and membrane peeling. Today this technique has become a standard procedure. The aim of this study was to evaluate the role of optical coherence tomography in diagnosing and staging, as well as in predicting, the functional and anatomical outcome after macular hole surgery. METHOD: In a prospective study 94 consecutive patients (20 male, 74 female) with a mean age of 67.6 (SD 6.0) years and a macular hole stage II (n = 8), III (n = 72), and IV (n = 14) according to the classification by Gass were examined with optical coherence tomography (OCT) before pars plana vitrectomy. Macular hole diameters were determined at the level of the retinal pigment epithelium (base diameter) and at the minimal extent of the hole (minimum diameter). Calculated hole form factor (HFF) was correlated with the postoperative anatomical success rate and best corrected visual acuity. The duration of symptoms was correlated with base and minimum diameter of the macular hole. RESULTS: In eyes without anatomical closure of the macular hole after one surgical approach (13/94) the base diameter (p1) and the minimum diameter (p2) were significantly larger than in cases with immediate postsurgical closure (p1 = 0.003; p2 = 0.028). There was a significant negative correlation between both the base and the minimum diameter of the hole and the postoperative visual function (p1 = 0.016; p2 = 0.002). In all patients with HFF >0.9 the macular hole was closed following one surgical procedure, whereas in eyes with HFF <0.5 anatomical success rate was 67%. Better postoperative visual outcome correlated with higher HFF (p = 0.050). There was no significant correlation between the duration of symptoms and base or minimum diameters (p1 = 0.053; p2 = 0.164), respectively. CONCLUSION: Preoperative measurement of macular hole size with OCT can provide a prognostic factor for postoperative visual outcome and anatomical success rate of macular hole surgery. The duration of symptoms did not correlate with the diameters measured. Base and minimum diameters especially seem to be of predictive value in macular hole surgery.
Aged↗
BLyS BINDS TO B CELLS WITH HIGH AFFINITY AND INDUCES ACTIVATION OF THE TRANSCRIPTION FACTORS NF-kappaB AND ELF-1.
B lymphocyte stimulator (BLyS) is a novel member of the TNF family of proteins expressed by myeloid cells as membrane-bound and soluble forms. BLyS was shown to act specifically on B cells, inducing proliferation and immunoglobulin production both in vitro and in vivo. The present study was undertaken to characterize binding of radiolabeled BLyS to its cognate receptor on human B lymphocytes and examine intracellular events initiated by BLyS binding. Similar to other TNF family members, BLyS is present in solution as a homotrimer as determined by gel filtration chromatography and light scattering analysis. BLyS binding to B cells is specific as other TNF family members tested did not compete for(125)I-BLyS binding. Analysis of equilibrium binding of(125)I-labeled BLyS to purified human tonsillar B cells demonstrated saturable binding. Scatchard analysis of the binding data revealed a single class of high-affinity binding on human B cells with approximately 2600 binding sites per cell and an apparent dissociation constant (K(D)) of about 0.1 nM. In addition we report that BLyS binding to B cells results in the activation of NF-kappaB and the Ets family transcription factor, ELF-1, and in the induction of mRNA for Polo-like kinase (PLK).
B-Cell Activating Factor↗
The expression and regulation of depolarization-activated K+ channels in the insulin-secreting cell line INS-1.
The aim of the present study was to characterize depolarization-activated outward currents in insulin-secreting INS-1 cells and to investigate the role of K+ channels other than the KATP channels in the regulation of insulin release. Outward currents were inhibited by 4-aminopyridine (4-AP, 10 mmol/l), tetraethylammonium (TEA, 10 mmol/l) and tetrapentylammonium (TPeA, 100 mumol/l) by 55.1 +/- 3.8% (n = 3), 78.1 +/- 3.2% (n = 6) and 98.7 +/- 0.8% (n = 5), respectively. Margatoxin (5 nmol/l) and charybdotoxin (3 mumol/l) had no effect. 4-AP inhibited mainly a fast-activating, slowly inactivating current, whereas the TEA- and TPeA-sensitive current components were slowly activating and non-inactivating. Forskolin and the forskolin analogue 1,9-dideoxyforskolin, which does not stimulate adenylyl cyclase, also inhibited the outward current, suggesting a direct effect on the channels. Using reverse transcriptase polymerase chain reaction (RT/PCR). Kv channel mRNAs of Kv1.4, Kv1.5, Kv2.1, Kv2.2, Kv3.1 and Kv3.2 were detected whereas other Kv channels, Kv1.1, Kv1.2, Kv1.3, Kv1.6 and Kv3.4 were not detected. Insulin secretion in the presence of tolbutamide (100 mumol/l) was increased by 4-AP, TEA and TPeA by 65%, 41% and 150%, respectively. Basal secretion was not affected by these blockers. Our study reveals that the opening of voltage-dependent K+ channels negatively controls insulin secretion in depolarized cells, probably by shortening the action potential thus reducing Ca2+ influx.
1-Methyl-3-isobutylxanthine↗
Central corneal thickness measurement with a retinal optical coherence tomography device versus standard ultrasonic pachymetry.
PURPOSE: To demonstrate the capability of a standard, commercially available optical coherence tomography device (originally designed to measure retinal thickness) to image the human cornea in vivo and to measure central corneal thickness (CCT) in normal and edematous corneas. The intrapatient precision and interpatient variability of this novel application was compared to standard ultrasonic pachymetry. Also, the correlation of both methods was investigated. METHODS: CCT measurements using optical coherence tomography (OCT) and ultrasonic pachymetry (PACH) were obtained in 36 normal eyes and 16 eyes with corneal edema. RESULTS: Direct in vivo imaging of the cornea and measurements of CCT by OCT could be performed in all eyes. In normal subjects, CCT(OCT) was 530+/-32 microm and CCT(PACH) was 581+/-34 microm. The two methods showed a highly significant correlation with a standardized regression coefficient of 0.988. The difference between both methods was constant over the range of CCT (mean difference, 49.4+/-5.9 microm). The mean intrapatient SD of CCT measurements was 4.90 microm and 4.96 microm for OCT and PACH, respectively. In patients with corneal edema, mean CCT(OCT) was 601+/-59 microm, and mean CCT(PACH) was 667+/-68 microm. The difference between the two techniques increased slightly with increasing corneal edema (mean difference, 66.9+/-10.9 microm). CONCLUSION: Imaging of the human cornea can be performed by a standard retinal OCT device, and OCT measurement of CCT shows excellent correlation to values obtained by PACH, giving similar readings separated by a constant difference. In corneal edema, the difference between the two methods is additionally increased, but continues to demonstrate excellent consistency.
Adult↗
Comparison of foveal thickness measured with the retinal thickness analyzer and optical coherence tomography.
PURPOSE: To assess and compare the reliability and reproducibility of retinal thickness measurements for the retinal thickness analyzer (RTA) and optical coherence tomography (OCT) in normal and edematous retina. METHODS: The authors measured the foveal thickness of 21 normal eyes and 9 eyes with macular edema with both methods in random order. With the RTA, the fovea was measured 10 times; with the OCT, six scans (one horizontal and five vertical cross-sections) of the fovea were obtained. RESULTS: Mean foveal thickness of normal eyes measured 153 microm with OCT and 181 microm with RTA (median for both methods 150 microm). Coefficients of variation (CV) within the same subjects were 10% (OCT) and 9% (RTA) reducing to 9% (OCT) and 7% (RTA) when scans were repeated only five times for both methods. The RTA, however, yielded an interpatient CV of 33% (OCT 17%), which was caused by several falsely high readings in normal individuals. In eyes with retinal thickening the OCT measured a mean of 324 microm with 15% intra- and 58% interpatient CV. The RTA yielded a mean of 403 microm with CV of 18% and 73%, respectively. CONCLUSION: Both methods yield reproducible measurements of foveal thickness in normal individuals and individuals with macular edema. However, falsely high measurements may occur with the RTA, reducing its reliability as compared to the OCT.
Anthropometry↗
Loss of annexin A7 leads to alterations in frequency-induced shortening of isolated murine cardiomyocytes.
Annexin A7 has been proposed to function in the fusion of vesicles, acting as a Ca(2+) channel and as Ca(2+)-activated GTPase, thus inducing Ca(2+)/GTP-dependent secretory events. To understand the function of annexin A7, we have performed targeted disruption of the Anxa7 gene in mice. Matings between heterozygous mice produced offspring showing a normal Mendelian pattern of inheritance, indicating that the loss of annexin A7 did not interfere with viability in utero. Mice lacking annexin A7 showed no obvious phenotype and were fertile. To assay for exocytosis, insulin secretion from isolated islets of Langerhans was examined. Ca(2+)-induced and cyclic AMP-mediated potentiation of insulin secretion was unchanged in the absence of annexin A7, suggesting that it is not directly implicated in vesicle fusion. Ca(2+) regulation studied in isolated cardiomyocytes, showed that while cells from early embryos displayed intact Ca(2+) homeostasis and expressed all of the components required for excitation-contraction coupling, cardiomyocytes from adult Anxa7(-/-) mice exhibited an altered cell shortening-frequency relationship when stimulated with high frequencies. This suggests a function for annexin A7 in electromechanical coupling, probably through Ca(2+) homoeostasis.
Animals↗
Assessment of phalangeal bone loss in patients with rheumatoid arthritis by quantitative ultrasound.
OBJECTIVE: Periarticular osteopenia is an early radiological sign of rheumatoid arthritis (RA). Quantitative ultrasound (QUS) devices have recently been shown to be useful for assessing osteoporosis. In this study the capability of a transportable and easy to use QUS device to detect skeletal impairment of the finger phalanges in patients with RA was investigated. METHODS: In a cross sectional study 83 women (30 controls, 29 with glucocorticosteroid (GC) treated RA, and 24 with GC treated vasculitis) were examined. QUS measurements were obtained at the metaphyses of the proximal phalanges II-V and directly at the proximal interphalangeal joints II-IV with a DBM Sonic 1200 (IGEA, Italy) QUS device. Amplitude dependent speed of sound (AD-SoS) was evaluated. In 23 of the patients with RA, hand radiographs were evaluated. RESULTS: Significant differences between patients with RA and the other groups were found for AD-SoS at both measurement sites. Compared with age matched controls, the AD-SoS of patients with RA was lowered by two and three standard deviations at the metaphysis and joint, respectively. Fingers of patients with RA without erosions (Larsen score 0-I) already had significantly decreased QUS values, which deteriorated further with the development of erosions (Larsen II-V). CONCLUSION: This study indicates that QUS is sensitive to phalangeal periarticular bone loss in RA. QUS is a quick, simple, and inexpensive method free of ionising radiation that appears to be suited to detection of early stages of periarticular bone loss. Its clinical use in the assessment of early RA should be further evaluated in prospective studies.
Adult↗
Modulation of T-cell responses to alloantigens by TR6/DcR3.
TR6 (DcR3) is a new member of the TNF receptor (TNFR) family that lacks a transmembrane domain in its sequence, indicating that it is a secreted molecule. TR6 can bind to FasL and prevent FasL-induced apoptosis; it can also associate with LIGHT, another TNF family member. The role of TR6 in immune responses was investigated in this study. According to flow cytometry, recombinant human TR6-Fc binds to human LIGHT expressed on 293 cells or on activated human T cells and competes with the LIGHT receptor TR2 for the binding to LIGHT on these cells. Human TR6 could cross-react with mouse LIGHT in immunoprecipitation. TR6-Fc also downregulates cytotoxic T lymphocyte activity in vitro and graft-versus-host responses in mice. Moreover, TR6-Fc modulates lymphokine production by alloantigen-stimulated mouse T cells. TR6-Fc ameliorated rejection response to mouse heart allograft. These results indicate that TR6 can dampen T-cell responses to alloantigens. Such regulatory effects of TR6 probably occur via interference with interaction between pairs of related TNF and TNFR family members, LIGHT/TR2 being one of the possible candidate pairs.
Animals↗
Personality disorders in offenders: categorical versus dimensional approaches.
The present study focused on the consequences of cut-off scores in personality disorder diagnoses for their association with criminal behavior. Using ICD-10 personality disorder criteria eliminating offence-related symptoms, we studied the distributions of categorically diagnosed personality disorders and of dimensional personality disorder scores in a group of offenders and a noncriminal control group. Whereas the dimensional scores of the offender group differed significantly from those of the control group for all personality disorders under study, the frequency of categorical diagnoses differed significantly for two personality for two personality disorders only. Moreover, prediction of group membership (offenders vs. nonoffenders) from personality disorder scores was substantially more precise than prediction from categorical diagnoses. It is concluded that a dimensional approach to personality disorder diagnosis is not only superior theoretically but also yields more precise information about the specific associations with criminal behavior.
Adult↗
In vivo inhibition of Fas ligand-mediated killing by TR6, a Fas ligand decoy receptor.
TR6, a member of the tumor necrosis factor (TNF) receptor superfamily, has recently been shown to bind to Fas ligand (FasL) and inhibit FasL-mediated cell killing in vitro. In the current study, we demonstrate that TR6 can block the lethal activity of FasL in multiple in vitro systems, and extend this finding to an in vivo model of hepatitis. The binding of human TR6 to human FasL was verified with BIAcore chip technology. Human primary hepatocytes, HT-29 cells and Jurkat cells were assayed for viability to demonstrate TR6 inhibition of FasL-mediated cytotoxicity in vitro. Human TR6 was also shown to cross-react with membrane-bound mouse FasL, since the in vitro cytotoxic activity of L929 cells transfected with murine FasL was inhibited in the presence of human TR6. In vivo, FasL-induced acute, lethal, fulminant hepatic apoptosis resulting in death within 2 h of intravenous injection into Fas+ mice, but not Fas- MRL/lpr mice. Pretreatment of mice with TR6 blocked FasL-induced mortality, presumably by attenuating FasL-induced hepatic apoptosis. Thus, in both in vitro and in vivo systems, TR6 acts as a functional FasL decoy receptor and may be clinically useful in the treatment of hepatitis and other diseases associated with FasL-mediated tissue injury.
Animals↗