Efficacy of a hybrid technique of simultaneous videolaryngoscopy with flexible bronchoscopy in children with difficult direct laryngoscopy in the Pediatric Difficult Intubation Registry.

Children with difficult tracheal intubation are at increased risk of severe complications, including hypoxaemia and cardiac arrest. Increasing experience with the simultaneous use of videolaryngoscopy and flexible bronchoscopy (hybrid) in adults led us to hypothesise that this hybrid technique could be used safely and effectively in children under general anaesthesia. We reviewed observational data from the international Pediatric Difficult Intubation Registry from 2017 to 2021 to assess the safety and efficacy of hybrid tracheal intubation approaches in paediatric patients. In total, 140 patients who underwent 180 attempts at tracheal intubation with the hybrid technique were propensity score-matched 4:1 with 560 patients who underwent 800 attempts with a flexible bronchoscope. In the hybrid group, first attempt success was 70% (98/140) compared with 63% (352/560) in the flexible bronchoscope group (odds ratio (95%CI) 1.4 (0.9-2.1), p = 0.1). Eventual success rates in the matched groups were 90% (126/140) for hybrid vs. 89% (499/560) for flexible bronchoscope (1.1 (0.6-2.1), p = 0.8). Complication rates were similar in both groups (15% (28 complications in 182 attempts) hybrid; 13% (102 complications in 800 attempts) flexible bronchoscope, p = 0.3). The hybrid technique was more likely than flexible bronchoscopy to be used as a rescue technique following the failure of another technique (39% (55/140) vs. 25% (138/560), 2.1 (1.4-3.2) p < 0.001). While technically challenging, the hybrid technique has success rates similar to other advanced airway techniques, few complications and may be considered an alternative technique when developing an airway plan for paediatric patients whose tracheas are difficult to intubate under general anaesthesia.

EGFR Protein Expression of KRAS Wild-Type Colorectal Cancer: Predictive Value of the Sidedness for Efficacy of Anti-EGFR Therapy.

Right- and left-sided colorectal cancers (RSCRC and LSCRC, respectively) are different developmentally, genetically and prognostically. Clinical data also indicate that they respond differently to anti-EGFR therapies. The role of EGFR protein expression in KRAS wild type colorectal cancer is also controversial. Here we have used a cohort of anti-EGFR antibody treated KRAS-wild type colorectal cancer patients (n = 97) to analyse the prognostic role of EGFR protein expression in relation to sidedness. In our cohort EGFR copy number, determined by FISH, was not associated with the level of EGFR protein, assessed by immunohistochemistry and measured by H-scoring. There was a significantly higher EGFR H-score detected in RSCRC as compared to LSCRC in primary tumors (p = 0.04). Furthermore, in a proportion of cases (n = 31) metastatic tissues were also available and their analysis also found a significantly higher EGFR H-score in metastases of RSCRC compared to LSCRC (p = 0.018). Kaplan Meyer survival analysis demonstrated that anti-EGFR antibody therapies were more effective in case of LSCRC compared to RSCRC. Although in case of progression-free survival data just indicated a trend (p = 0.065), in case of overall survival the difference was significant favouring LSCRC (p = 0.047). These data demonstrated for the first time that the EGFR protein expression is significantly higher in KRAS wild type RSLCL as compared to LSCRC. Meanwhile it is somewhat unexpected that the lower EGFR protein expression was found to be associated with better efficacy of anti-EGFR antibody therapies of colorectal cancer, the finding of which must be further validated.

ABCB1 and ABCG2 drug transporters are differentially expressed in non-small cell lung cancers (NSCLC) and expression is modified by cisplatin treatment via altered Wnt signaling.

BACKGROUND: Lung cancer (LC) is still the most common cause of cancer related deaths worldwide. Non-small cell lung cancer (NSCLC) accounts for 85% of all LC cases but is not a single entity. It is now accepted that, apart from the characteristic driver mutations, the unique molecular signatures of adeno- (AC) and squamous cell carcinomas (SCC), the two most common NSCLC subtypes should be taken into consideration for their management. Therapeutic interventions, however, frequently lead to chemotherapy resistance highlighting the need for in-depth analysis of regulatory mechanisms of multidrug resistance to increase therapeutic efficiency. METHODS: Non-canonical Wnt5a and canonical Wnt7b and ABC transporter expressions were tested in primary human LC (n = 90) resections of AC and SCC. To investigate drug transporter activity, a three dimensional (3D) human lung aggregate tissue model was set up using differentiated primary human lung cell types. Following modification of the canonical, beta-catenin dependent Wnt pathway or treatment with cisplatin, drug transporter analysis was performed at mRNA, protein and functional level using qRT-PCR, immunohistochemistry, immune-fluorescent staining and transport function analysis. RESULTS: Non-canonical Wnt5a is significantly up-regulated in SCC samples making the microenvironment different from AC, where the beta-catenin dependent Wnt7b is more prominent. In primary cancer tissues ABCB1 and ABCG2 expression levels were different in the two NSCLC subtypes. Non-canonical rhWnt5a induced down-regulation of both ABCB1 and ABCG2 transporters in the primary human lung aggregate tissue model recreating the SCC-like transporter pattern. Inhibition of the beta-catenin or canonical Wnt pathway resulted in similar down-regulation of both ABC transporter expression and function. In contrast, cisplatin, the frequently used adjuvant chemotherapeutic agent, activated beta-catenin dependent signaling that lead to up-regulation of both ABCB1 and ABCG2 transporter expression and activity. CONCLUSIONS: The difference in the Wnt microenvironment in AC and SCC leads to variations in ABC transporter expression. Cisplatin via induction of canonical Wnt signaling up-regulates ABCB1 and ABCG2 drug transporters that are not transporters for cisplatin itself but are transporters for drugs that are frequently used in combination therapy with cisplatin modulating drug response.

Increased Wnt5a in squamous cell lung carcinoma inhibits endothelial cell motility.

BACKGROUND: Angiogenesis is important both in normal tissue function and disease and represents a key target in lung cancer (LC) therapy. Unfortunately, the two main subtypes of non-small-cell lung cancers (NSCLC) namely, adenocarcinoma (AC) and squamous cell carcinoma (SCC) respond differently to anti-angiogenic e.g. anti-vascular endothelial growth factor (VEGF)-A treatment with life-threatening side effects, often pulmonary hemorrhage in SCC. The mechanisms behind such adverse reactions are still largely unknown, although peroxisome proliferator activator receptor (PPAR) gamma as well as Wnt-s have been named as molecular regulators of the process. As the Wnt microenvironments in NSCLC subtypes are drastically different, we hypothesized that the particularly high levels of non-canonical Wnt5a in SCC might be responsible for alterations in blood vessel growth and result in serious adverse reactions. METHODS: PPARgamma, VEGF-A, Wnt5a, miR-27b and miR-200b levels were determined in resected adenocarcinoma and squamous cell carcinoma samples by qRT-PCR and TaqMan microRNA assay. The role of PPARgamma in VEGF-A expression, and the role of Wnts in overall regulation was investigated using PPARgamma knock-out mice, cancer cell lines and fully human, in vitro 3 dimensional (3D), distal lung tissue aggregates. PPARgamma mRNA and protein levels were tested by qRT-PCR and immunohistochemistry, respectively. PPARgamma activity was measured by a PPRE reporter system. The tissue engineered lung tissues expressing basal level and lentivirally delivered VEGF-A were treated with recombinant Wnts, chemical Wnt pathway modifiers, and were subjected to PPARgamma agonist and antagonist treatment. RESULTS: PPARgamma down-regulation and VEGF-A up-regulation are characteristic to both AC and SCC. Increased VEGF-A levels are under direct control of PPARgamma. PPARgamma levels and activity, however, are under Wnt control. Imbalance of both canonical (in AC) and non-canonical (in SCC) Wnts leads to PPARgamma down-regulation. While canonical Wnts down-regulate PPARgamma directly, non-canonical Wnt5a increases miR27b that is known regulator of PPARgamma. CONCLUSION: During carcinogenesis the Wnt microenvironment alters, which can downregulate PPARgamma leading to increased VEGF-A expression. Differences in the Wnt microenvironment in AC and SCC of NSCLC lead to PPARgamma decrease via mechanisms that differentially alter endothelial cell motility and branching which in turn can influence therapeutic response.

Decreased apopto-phagocytic gene expression in the macrophages of systemic lupus erythematosus patients.

The clearance of apoptotic cells has an important role in the maintenance of tissue homeostasis and in the protection of tissues from the inflammatory and immunogenic contents of dying cells. A defect in the recognition and phagocytosis of apoptotic cells contributes to the development of chronic inflammation and autoimmune disorders. We have observed that compared with healthy donors, differentiated macrophages from patients with untreated systemic lupus erythematosus (SLE) showed decreased phagocytosis of apoptotic neutrophils. A TaqMan Low Density Array was designed to determine the mRNA expression levels of 95 apopto-phagocytic genes in differentiated non-phagocytosing and phagocytosing macrophages. In the macrophages of clinically and immunoserologically active SLE patients, 39 genes were expressed at lower levels than in the control macrophages. When inactive patients were compared with those with minor immunoserological abnormalities or patients in an immunoserologically active state, a relationship was observed between the altered gene expression profile and the disease state. In the macrophages of patients with engulfing apoptotic cells, an upregulation of genes involved in inflammation, autophagy, and signaling was observed. These results indicate that novel immune-pathological pathways are involved in SLE and suggest targets for potential therapeutic modulation.

Aseptic necrosis at multiple localisations in a lupus patient with lymphoma.

Avascular or aseptic necrosis is a well-defined entity leading to the degradation of cellular elements of the bone. The pathogenesis of osteonecrosis (ON) is still unknown. There are two main types of ON: traumatic or non-traumatic. Several clinical entities could associate with ON, systemic diseases, environmental factors, pregnancy, systemic autoimmune or rheumatic diseases, thrombophilia, corticosteroid therapy, cytotoxic dugs, infections, metabolic and hematologic diseases, etc. Corticosteroids (CS) are still the most frequently used therapeutic options in the early phase and during flares of these diseases. Inflammatory cytokines and antibodies have been described to participate in the pathogenesis of ON. The infiltrative disorders of the bone marrow could also contribute to the development of ON. Hereby, we describe a female patient with NHL followed by SLE in whom ON has developed at least in two localisations. Lupus flare, long-term CS therapy, lymphoma relapse or the presence of antiphospholipid antibodies were excluded. Although the bi-localised ON could be contributed to immunologic factors or trauma, the exact aetiology in this case could not be elucidated.

Clinical and immunoserological characteristics of the transition from primary to overlap antiphospholipid syndrome.

Antiphospholipid syndrome (APS) is a distinct clinical entity characterized by arterial and venous thromboembolic events, recurrent fetal loss and the presence of antiphospholipid antibodies in the patients' sera. In primary APS, there is no detectable underlying disease, while overlap APS is associated with clinical syndromes including systemic autoimmune diseases, infections, or malignancies. We carried out a retrospective analysis of serological and clinical manifestations as well as assessed outcome-measures in 165 patients with primary APS. Thrombotic manifestations and possible signs of autoimmune diseases were determined at the time of the diagnosis, followed by the analysis of recurrent thrombotic events and effects of therapy during the follow-up period. Among the 165 patients with primary APS at onset, 105 patients (63%) remained primary APS after a mean 5.2 years of follow-up. In 14% of the patients, subsequently APS became associated with various characteristics of undifferentiated connective tissue disease. Finally 23% of patients evolved into a definitive systemic autoimmune disease during a mean 9.75 years of follow-up. Recurrent thrombotic events were registered in 24% of patients. Our results suggest that primary APS may be considered as a potential early phase of a dynamic transition towards a well-defined systemic autoimmune disease.

Disease activity and damage accrual during the early disease course in a multinational inception cohort of patients with systemic lupus erythematosus.

An inception cohort of patients with systemic lupus erythematosus from 14 European centres was followed for up to 5 years in order to describe the current early disease course. At inclusion patients (n = 200, 89% female, mean age 35 years, 97% Caucasian, mean SLEDAI 12.2) fulfilled a mean of 6.5 ACR classification criteria. The most prevalent criteria were antinuclear Ab presence (97%) followed by anti-dsDNA Ab (74%), arthritis (69%), leukocytopenia (54%) and malar rash (53%), antiphospholipid Ab (48%) and anti-synovial membrane Ab (21.6%). Clinical signs of lupus nephritis (LN) were present in 39% with biopsy-confirmed LN seen in 25%. Frequent additional findings were hypocomplementaemia (54%), anti-SSA Ab (49%), alopecia (26%) and Raynaud's phenomenon (31%). There were few regional differences in disease presentation and management. One and 5-year survival rates were 99% and 97% respectively. During the mean follow-up of 4.1 years 25% entered a state of early disease quiescence by global physician assessment, but the overall risk of subsequent flare was 60%. Maximum SLEDAI scores decreased over time, but 45% of patients accrued damage (SDI >or=1) for which baseline presence of proteinuria and persistent disease activity were independent predictors. The results indicate minor differences in SLE presentation and treatment within various regions of Europe and a high diagnostic reliance on anti-dsDNA Ab. Despite early reductions in disease activity and improved mortality, the risk for disease flare and damage development is, however, still substantial, especially in patients not entering an early remission.

Modification of poly(lactic/glycolic acid) surface by chemical attachment of poly(ethylene glycol).

Biodegradable polyesters such poly(lactic acid) and poly(lactic/glycolic acid) (PLGA) copolymers are preferred biomaterials and used among others as drug delivery systems, although their surface hydrophobicity limits their application. In this work, chemical modification of the PLGA surface was developed by coupling of either linear or starlike poly(ethylene glycol) (PEG) molecules via chemical bonds to the PLGA surface following amino functionalization as a first step to improve its biocompatibility. The chemical attachment was followed by detailed X-ray photoelectron spectroscopy (XPS) studies. It was shown that substantial modification can be achieved by linear PEG, but even higher surface coverage with hydrophilic groups can be obtained when the six-armed PEG is applied with the additional advantage of possible further functionalization via free amino groups available on the surface of the latter. As a final goal, a significant increase of water wettability together with reduced protein adsorption was achieved on PEG-coupled PLGA surfaces.

Toxicogenomic analysis of N-nitrosomorpholine induced changes in rat liver: comparison of genomic and proteomic responses and anchoring to histopathological parameters.

A common animal model of chemical hepatocarcinogenesis was used to examine the utility of transcriptomic and proteomic data to identify early biomarkers related to chemically induced carcinogenesis. N-nitrosomorpholine, a frequently used genotoxic model carcinogen, was applied via drinking water at 120 mg/L to male Wistar rats for 7 weeks followed by an exposure-free period of 43 weeks. Seven specimens of each treatment group (untreated control and 120 mg/L N-nitrosomorpholine in drinking water) were sacrificed at nine time points during and after N-nitrosomorpholine treatment. Individual samples from the liver were prepared for histological and toxicogenomic analyses. For histological detection of preneoplastic and neoplastic tissue areas, sections were stained using antibodies against the placental form of glutathione-S-transferase (GST-P). Gene and protein expression profiles of liver tissue homogenates were analyzed using RG-U34A Affymetrix rat gene chips and two-dimensional gel electrophoresis-based proteomics, respectively. In order to compare results obtained by histopathology, transcriptomics and proteomics, GST-P-stained liver sections were evaluated morphometrically, which revealed a parallel time course of the area fraction of preneoplastic lesions and gene plus protein expression patterns. On the transcriptional level, an increase of hepatic GST-P expression was detectable as early as 3 weeks after study onset. Comparing deregulated genes and proteins, eight species were identified which showed a corresponding expression profile on both expression levels. Functional analysis suggests that these genes and corresponding proteins may be useful as biomarkers of early hepatocarcinogenesis.

Erythropoiesis-stimulating agent withdrawal and oxidative stress in hemodialysis.

AIMS: Variation of the action of erythropoiesis-stimulating agent (ESA) may modify oxidative stress in hemodialyzed (HD) patients. Our aim was to follow changes of oxidative stress during withdrawal and subsequent resumption of ESA therapy. PATIENTS AND METHODS: After a 14-day suspension of epoietin-beta treatment, 11 HD patients received epoietin-beta and 10 patients darbepoietin-alpha. The whole blood oxidized and reduced glutathione (GSSG, GSH) and erythrocyte malondialdehyde (E-MDA) concentrations and the erythrocyte superoxide dismutase (E-SOD) and catalase (E-CAT) activities were determined before the ESA-free interval (baseline) and at Weeks 2, 6, 10 and 14. RESULTS: In both groups, the ratios GSSG/ GSH were increased at Weeks 2 and 6 (p < 0.001). The E-MDA levels were elevated (p < 0.01) and the E-SOD activities were decreased (p < 0.001) at Week 6. By Week 14, these markers had returned to the baseline, whereas the GSH (p < 0.001) and E-CAT activity levels (p < 0.001) had increased. CONCLUSIONS: An increase in oxidative stress was revealed by the ratio GSSG/GSH directly after the short-term withdrawal of epoietin-b therapy in HD. This new finding may have implications in conditions involving transiently depressed ESA action. For both ESAs, the early phase of readministration was associated with similarly increased oxidative stress, with a subsequent return to the baseline level.

Cytokine Genes TNF, IL1A, IL1B, IL6, IL1RN and IL10, and childhood-onset mood disorders.

BACKGROUND/AIMS: Inflammatory cytokines induce a behavioral syndrome, known as sickness behavior, that strongly resembles symptoms typically seen in depression. This resemblance has led to the theory that an imbalance of inflammatory cytokine activity may be a contributing factor in depressive disorders. Support for this is found in multiple lines of evidence, such as the effects of cytokines on the activities of the hypothalamic-pituitary-adrenal axis, serotonin and brain-derived neurotrophic factor, and hippocampal function, all of which are implicated in the etiology of depression. In addition, associations between inflammatory activity and depressive symptomology have been documented in a number of studies, and the depressogenic effects of cytokine therapy are well known. Accordingly, given that depression has a substantial genetic basis, genes involved in the regulation of inflammatory cytokine activity are strong candidates for involvement in genetic susceptibility to depressive disorders. Here, we have tested 6 key genes of this type, TNF, IL1A, IL1B, IL6, IL1RN and IL10, as candidates for involvement in childhood-onset mood disorders. METHODS: In this study of 384 families, each ascertained through a child with depression diagnosed before the age of 15 years, 11 polymorphisms of known or likely functional significance (coding and regulatory variants) were analyzed. RESULTS: Testing for biased transmission of alleles from parents to their affected offspring, we found no evidence for an association between childhood-onset mood disorders and any of the polymorphisms, either individually or as haplotypes. CONCLUSION: The present study does not support the involvement of the TNF, IL1A, IL1B, IL6, IL1RN and IL10 variants as major genetic risk factors contributing to early-onset mood disorders.

A novel synthetic peptide polymer with cyclic RGD motifs supports serum-free attachment of anchorage-dependent cells.

Cell adhesivity is a basic biological principle, which provides mechanisms for construction of multicellular organisms, tissue genesis, migration and individual cell survival. In vivo, the cell adhesive environment is provided by extracellular matrix molecules, neighboring cell surfaces and soluble factors delivered either by tissue cells or by blood circulation. The exact molecular composition of the microenvironment of a cell is not properly understood. The nondefined molecular composition of "native" adhesive components hinders their application when defined culture conditions are necessary, as, for an example, growing human cells for further clinical application. Applying large, substrate-coating molecules as backbones for carrying specific adhesive peptide motifs provides a relatively cheap, reproducible, and chemically defined group of synthetic adhesion molecules. Here, we report on the design, synthesis, and testing of a novel cyclic RGD-containing coating material, which promotes initial attachment, spreading, survival, and proliferation of a number of different cell types. The potent adhesive polypeptide-brush, composed of poly[Lys(DL-Ala(m))] branched chain polypeptide (AK) and multiple copies of cyclic(arginyl-glycyl-aspartyl-D-phenylalanyl-cysteine) pentapeptide prevents anoikis and supports cell attachment in the absence of serum or other biological additives. The defined conditions for cell maintenance make this material a promising candidate for coating artificial cell substrates even for therapeutic applications.

Complex care by multiple medical and dental specialists of a patient with aggressive Gorlin-Goltz syndrome.

Gorlin-Goltz syndrome is a genetically predisposed disease characterised by multiple basal cell carcinomas, odontogenic keratocysts and ectopic calcifications. The aim of this study was to show successful treatment of a 37-year-old male patient by cooperation between different dental and medical specialists. Because of the recurrence of a large basal cell carcinoma after multiple operations and a total dose telecobalt irradiation of 66 Gy, the patient's nose was ablated, with resection of the upper lip and part of the maxilla. The intraoral prosthetic treatment helped to restore the subtotal edentulousness. In order to enhance the application of the dental prosthesis, an Abbe plasty was performed at the second stage of surgery. As previous irradiation of the area precluded the use of facial implants immediately after the intraoral treatment, a temporary artificial nose prosthesis was created. The patient tolerated the procedures well and is completely disease-free 12 months after the surgery. Besides presenting a rare and complicated case of Gorlin-Goltz syndrome, the main purpose of this report is to show that, if different specialists in a dental-clinical team (maxillofacial surgeon, oncologist, radiation oncologist, prosthodontist and psychiatrist) combine their skills and expertise, successful management is possible even in a challenging complex case.

Successful rituximab-CHOP treatment of systemic lupus erythematosus associated with diffuse large B-cell non-Hodgkin lymphoma.

The authors discuss the case of a 76-year-old female patient who has been suffering from subacute cutaneous lupus erythematosus since 1983. In 1999 she was diagnosed with systemic lupus erythematosus (SLE) based on her symptoms of malar rash, polyarthritis, leukopenia, autoimmune hemolytic anemia and positive anti-DNA antibody test. For this she received methylprednisolone and cyclophosphamide. After 3 years of remission, symptoms of cutaneous vasculitis appeared in 2004, which transitionally responded to treatment with azathioprin and methylprednisolone. Her cutaneous symptoms, however, progressed quickly along with generalized lymphadenopathy, splenomegaly and thrombocytopenia. Immunohistological evaluation of the lymph node biopsy showed diffuse large B-cell lymphoma. She developed complete remission after treatment with six-cycle R-CHOP (rituximab, and reduced doses of cyclophosphamide, vincristin, adriablastin, methylprednisolone). SLE became inactive and her symptoms of vasculitis resolved. The authors are bringing attention to one of the possible late complications of systemic lupus, and also underscoring that treatment with rituximab (+CHOP) was beneficial not only for the lymphoma but the SLE as well.

Beneficial effects of CCR1 blockade on the progression of chronic renal allograft damage.

The biology of chemokines and their receptors have been linked to the development of chronic allograft damage. Effects of CCR1 antagonist BX 471 were studied in a Fischer to Lewis renal transplantation model at days 10, 21 and 42 after transplantation. BX 471 treatment did not effectively reduce signs of acute rejection at day 10 but significantly improved allograft function and morphology at day 21 posttransplantation. When therapy was initiated on day 21 after transplantation, glomerulosclerosis and tubulointerstitial fibrosis were significantly inhibited by day 42 posttransplantation. Parallel decrease in infiltrating and proliferating mononuclear cells (ED1, CD8 and Ki67) was observed in treated allografts. Expression of acute phase reactive and proinflammatory genes (HO-1, osteopontin) and molecules associated with fibrosis (PAI-1, TGF-beta1, biglycan) was downregulated at day 21; reduced collagen deposition was observed, parallel to a significant lower number of alpha-SMA+ interstitial myofibroblasts. In situ hybridization demonstrated that biglycan expression was reduced following CCR1 blockade in interstitium of treated allografts. CCR1 antagonism was found to inhibit CCL5-induced secretion of biglycan by macrophages in vitro. CCR1 blockade significantly inhibited development and progression of chronic allograft damage. CCR1 antagonists may represent a therapeutic option for chronic inflammation and fibrosis in renal grafts.

Significant correlation between the CD63 assay and the histamine release assay in chronic urticaria.

BACKGROUND: Antibodies directed to the alpha subunit of the high affinity IgE receptor and the IgE molecule are proposed to be of pathogenetic relevance in a group of patients with chronic urticaria (CU). The diagnosis of autoimmune chronic urticaria (ACU) is difficult; the autologous serum skin test (ASST) seems to be a useful screening test, but reliable, additional confirmatory methods are needed. OBJECTIVES: To assess the diagnostic value of a modified serum-induced basophil activation test, the CD63 expression assay, in the diagnosis of ACU by comparing the results of the CD63 assay with the results of the histamine release (HR) test, the ASST and serum levels of soluble CD40 ligand (sCD40L). METHODS: Using basophils from an atopic (DA) and a nonatopic (DNA) donor the activity of sera of 72 patients with CU were measured in HR assay by enzyme-linked immunosorbent assay and in CD63 expression assay by flow cytometry. An ASST was carried out in all patients; in 30 of the 72 patients sCD40L was detected and correlations were derived between the different assays. Sera of 20 normal controls and 26 patients with systemic autoimmune diseases were also tested in the HR assay and in the CD63 expression assay. RESULTS: Histamine-releasing activity was detected in the sera of 51% (DA) and 32% (DNA) of CU patients and 57% (DA) and 28% (DNA) of sera upregulated CD63 expression on the surface of basophils from the different donors. There was a significant correlation between the HR and the CD63 assays carried out on both donors, but the ASST showed a strong correlation with the HR assay only for basophils from the DA. The serum level of sCD40L was significantly higher in patients with CU compared with controls, but the difference between the autoimmune and the nonautoimmune groups was not significant. CONCLUSIONS: The CD63 expression assay seems to be a reliable functional test in the diagnosis of ACU, particularly if highly sensitive donor basophils are used, but the determination of the sCD40L serum level was not sufficient to differentiate between the autoimmune and the nonautoimmune patient groups.

Ultraviolet-A1 phototherapy modulates Th1/Th2 and Tc1/Tc2 balance in patients with systemic lupus erythematosus.

OBJECTIVE: Ultraviolet-A1 (UVA1) phototherapy is effective for a variety of dermatological diseases. We examined the effectiveness and reliability of low-dose UVA1 phototherapy (60 kJ/m2/treatment) in patients suffering from systemic lupus erythematosus (SLE). We studied the changes in immunological parameters. METHODS: The patients received a 9-week course of phototherapy according to the following regimen: five times a week during the first 3 weeks, three times a week during the second 3 weeks and twice during the last 3 weeks. Among other things, we analysed the proportions of T helper 1 (Th1), Th2, T cytotoxic (Tc1) and Tc2 cell populations in the peripheral blood of patients by flow cytometric detection of intracytoplasmic interferon gamma (IFN-gamma) and interleukin 4 (IL-4). RESULTS: Our study showed the improvement of clinical symptoms determined by the subjective clinical disease activity scoring and the SLE Disease Activity Index (SLEDAI). By the end of UVA1 phototherapy, the mean value of SLEDAI had decreased from 7.2+/-5.6 to 0.9+/-1.8, which was significant (P = 0.005). Immunological investigations detected a decrease in the frequency of IFN-gamma-producing Th1 and Tc1 cells and a decrease in the Th1/Th2 and Tc1/Tc2 ratios after UVA1 therapy. CONCLUSION: According to the literature, IFN-gamma has a pathogenic role in the development of SLE. We observed a decreased proportion of IFN-gamma-secreting cells, which we think is presumably one of the beneficial effects of UVA1 therapy. On the basis of our study, UVA1 phototherapy does seem to be an effective adjuvant in the treatment of SLE patients.

[Autoimmune cholangitis with vasculitic ulcers, rheumatoid arthritis and IgA glomerulonephritis]. / Autoimmuncholangitis mit vaskulitischen Ulzera, rheumatoider Arthritis und IgA-Glomerulonephritis.

HISTORY AND ADMISSION FINDINGS: A 51-year-old woman was admitted because of relapsing episodes of fever and leg ulcers for 14 years. In addition, she had polyserositis, polyarthralgias and polyarthritides, renal failure with proteinuria and elevation of gamma-GT and alkaline phosphatase. The patient was in a reduced general condition and cachectic nutritional state. She had slight scleral icterus, the liver being palpable 5 cm under the costal margin, edema of the lower limbs and two ulcers at the right foot. INVESTIGATIONS: Laboratory examinations revealed leukocytosis, anemia, elevation of cholestasis and inflammation parameters as well as renal failure. During a 24 hour collection period, a significant proteinuria was demonstrated. Immunoserologically, an ANA titer of 1:100 and a positive rheumatoid factor were found, ANCAs and AMAs were negative. On ultrasound, both kidneys exhibited a blurred pelvic parenchymal border. Thyroid ultrasound demonstrated parenchymal changes consistent with Hashimoto's disease. Ultrasound of the wrist revealed extensive arthritis with tendovaginitis. A renal biopsy revealed mesangioproliferative glomerulonephritis. DIAGNOSIS, THERAPY AND CLINICAL COURSE: Due to serologically persistent cholestasis, a liver biopsy was performed which, together with negative AMAs, revealed the diagnosis of an autoimmune cholangitis (AIC; AMA-negative primary-biliary cirrhosis (PBC)). In addition, the patient presented with rheumatoid arthritis, polyserositis, IgA glomerulonephritis, vasculitic leg ulcers and Hashimoto's thyreoiditis which were interpreted as extra-hepatic manifestations of the AIC. After initiation of high dosage corticosteroid therapy, rapid healing of the leg ulcers occurred. Therapy of the AIC consisted in ursodeoxycholic acid. CONCLUSION: The multitude of associated immunological phenomena in this patient resulted in a delay of the diagnosis. A AIC/PBC, however, should, always be considered in case of cholestasis.