Behavior of plasminogen at the luminal surface of the normal and deendothelialized rabbit aorta in vivo and in vitro

The behavior of purified rabbit plasminogen at the luminal surface of the uninjured and deendothelialized rabbit aorta has been studied in vivo and in vitro. After intravenous injection, 125I-plasminogen associated rapidly with the endothelium (approximately 0.1 pmol/cm2 at saturation) and passed through to accumulate in the subendothelium. At two to 15 hours after injection, 11 to 15 times more radioactivity was associated with the subendothelium than with the endothelium. Removal of the endothelium by balloon catheter led to a rapid adsorption of 125I-plasminogen by the luminal surface of the vessel; saturation (9.1 pmol/cm2) was attained at ten to 20 minutes after deendothelialization. Of the adsorbed plasminogen (radioactivity), only 2% to 4% was associated with the adherent platelet monolayer. Uptake of 125I- plasminogen by the deendothelialized vessel was not significantly inhibited by epsilon-aminohexanoic acid whether injected before or after the 125I-plasminogen. No evidence of plasmin activity at the aorta surface was found from either transmission electron microscopy studies or from amidolytic assays of plasminogen-saturated deendothelialized aorta samples before or after urokinase treatment. Balloon catheter treatment in vivo, however, generated significant antiplasmin activity of the deendothelialized aorta surface. We conclude that plasmin formed in vivo is probably inactivated by the antiplasmin activity that is associated with the subendothelium.     

Expression of adhesion molecules on CD34+ cells: CD34+ L-selectin+ cells predict a rapid platelet recovery after peripheral blood stem cell transplantation

Adhesion molecules play a role in the migration of hematopoietic progenitor cells and regulation of hematopoiesis. To study whether the mobilization process is associated with changes in expression of adhesion molecules, the expression of CD31, CD44, L-selectin, sialyl Lewisx, beta 1 integrins very late antigen 4 (VLA-4) and VLA-5, and beta 2 integrins lymphocyte function-associated 1 and Mac-1 was measured on either bone marrow (BM) CD34+ cells or on peripheral blood CD34+ cells mobilized with a combination of granulocyte colony- stimulating factor (G-CSF) and chemotherapy. beta 1 integrin VLA-4 was expressed at a significantly lower concentration on peripheral blood progenitor cells than on BM CD34+ cells, procured either during steady- state hematopoiesis or at the time of leukocytapheresis. No differences in the level of expression were found for the other adhesion molecules. To obtain insight in which adhesion molecules may participate in the homing of peripheral blood stem cells (PBSCs), the number of CD34+ cells expressing these adhesion molecules present in leukocytapheresis material was quantified and correlated with hematopoietic recovery after intensive chemotherapy in 27 patients. The number of CD34+ cells in the subset defined by L-selectin expression correlated significantly better with time to platelet recovery after PBSC transplantation (r = - .86) than did the total number of CD34+ cells (r = -.55). Statistical analysis of the relationship between the number of CD34+L-selectin+ cells and platelet recovery resulted in a threshold value for rapid platelet recovery of 2.1 x 10(6) CD34+ L-selectin+ cells/kg. A rapid platelet recovery (< or = 14 days) was observed in 13 of 15 patients who received > or = 2.1 x 10(6) CD34+ L-selectin+ cells/kg (median, 11 days; range, 7 to 16 days), whereas 10 of 12 patients who received less double positive cells had a relative slow platelet recovery (median, 20 days; range, 13 to 37 days). The L-selectin+ subpopulation of CD34+ cells also correlated better with time to neutrophil recovery (r = - .70) than did the total number of reinfused CD34+ cells (r = -.51). However, this latter difference failed to reach statistical significance. This study suggests that L-selectin is involved in the homing of CD34+ cells after PBSC transplantation.     

Blood cells participate in the fibrinolytic response to tissue-type plasminogen activator

Exercise and venous occlusion stimulate fibrinolysis. In addition to increased concentrations of tissue-type plasminogen activator (tPA) and increased plasmin-mediated fibrinolysis in plasma, these stimuli produce additional cellular-phase activity in blood that is of the same magnitude as the plasma response. To determine whether tPA alone, rather than other consequences of these stimuli, is responsible for the cellular response, the in vitro effects of tPA on whole blood, plasma, and calculated cellular-phase (whole blood minus plasma) activities were determined by solid-phase radiofibrin assay on venous blood from ten normal subjects (seven men, three women). At tPA concentrations encompassing physiological and therapeutic levels (5 to 100 ng/mL; 0.7 to 14 IU/mL), increments in whole blood were consistently in excess of those in companion plasma and represented increased cellular-phase activity equivalent in magnitude to the well-known increase in plasma activity. Fibrinolytic activity produced by 10 to 20 ng tPA/mL (1.4 to 2.8 IU/mL) was consistently detected in whole blood and plasma by 60 minutes, with higher concentrations (100 ng or 14 IU tPA/mL) detectable after a five-minute assay in all subjects. Thus, tPA alone, without invoking fibrinolytic factors extraneous to blood or other effects of exercise or venous occlusion, accounts for both cellular and plasma responses to these stimuli. The considerable cellular response, the mechanism of which remains to be elucidated, may constitute a determinant of individual therapeutic responsiveness to tPA.     

Probiotic Escherichia coli Nissle 1917 (EcN) for successful remission maintenance of ulcerative colitis in children and adolescents: an open-label pilot study

Since about 20 % of patients with ulcerative colitis (UC) are children and adolescents there is a need for therapeutic options custom-tailored to the children's needs. E. coli Nissle 1917 (EcN) as an evidence-based probiotic alternative to mesalazine (5-ASA) in adult UC remission maintenance is a promising agent for such a therapy. The present open-labelled pilot study was undertaken to investigate the clinical benefit of EcN for maintenance therapy in young UC patients. 34 patients with UC in remission aged between 11 and 18 years were allocated either to EcN (2 capsules o. d., n = 24) or 5-ASA (median 1.5 g/d, n = 10) and observed over one year. As a result, the relapse rate was 25 % (6 / 24) in the EcN group and 30 % (3 / 10) in the 5-ASA group. Data on the patients' global health and development were favourable and no serious adverse events were reported. In conclusion, maintenance therapy for UC with the probiotic EcN is effective also in young patients.     

On the nature of personal narratives of high quality

This investigation explores the discourse devices associated with high-quality personal narratives. The study examined normative characteristics of 11 high-quality personal narratives of a frightening experience identified (from a larger set of 72 narratives) for their effectiveness in engaging the audience. Lay ratings and an ethnographic interview with seven of the excellent storytellers further characterized the stories and validated their selection. Narratives of both African Americans and Caucasians were represented, and were similar in nature. The excellent narratives were longer, conveyed more fearful topics, and were more dramatic than average narratives. Drama was achieved through direct speech, prosodic shifts, voice changes, inclusion of multiple characters, repetition, and syntactic and semantic parallelism. Illustrative narrative excerpts are provided. This study illustrates the potential in pairing holistic and analytical approaches to narrative analysis.     

'Be active, eat right', evaluation of an overweight prevention protocol among 5-year-old children: design of a cluster randomised controlled trial

Background  

The prevalence of overweight and obesity in children has at least doubled in the past 25 years with a major impact on health. In 2005 a prevention protocol was developed applicable within Youth Health Care. This study aims to assess the effects of this protocol on prevalence of overweight and health behaviour among children.     

Preclinical evaluation of a monoclonal antibody targeting the epidermal growth factor receptor as a radioimmunodiagnostic and radioimmunotherapeutic agent

Background and purpose:

The studies described here are the first to evaluate the in vitro and in vivo properties of ¹¹¹In-CHX-A″-panitumumab for radioimmunotherapy (α- and β^--emitters) and radioimmunoimaging (single photon emission computed tomography and positron emission tomography).

Experimental approach:

Twenty-seven human carcinoma cell lines were analysed for expression of epidermal growth factor receptors by flow cytometry. Panitumumab was conjugated with CHX-A″-DTPA (diethylenetriamine-pentaacetic acid) and radiolabelled with ¹¹¹In. Immunoreactivity of the CHX-A″-DTPA-panitumumab and ¹¹¹In-CHX-A″-DTPA-panitumumab was evaluated by radioimmunoassays. Tumour targeting was determined in vivo by direct quantitation of tumour and normal tissues and by γ-scintigraphy.

Key results:

For 26 of 27 human tumour cell lines, 95% of the cells expressed epidermal growth factor receptors over a range of intensity. Immunoreactivity of panitumumab was retained after modification with CHX-A″-DTPA. Radiolabelling of the immunoconjugate with ¹¹¹In was efficient with a specific activity of 19.5 ± 8.9 mCi·mg⁻¹ obtained. Immunoreactivity and specificity of binding of the ¹¹¹In-panitumumab was shown with A431 cells. Tumour targeting by ¹¹¹In-panitumumab was demonstrated in athymic mice bearing A431, HT-29, LS-174T, SHAW or SKOV-3 s.c. xenografts with little uptake observed in normal tissues. The ¹¹¹In-panitumumab was also evaluated in non-tumour-bearing mice. Pharmacokinetic studies compared the plasma retention time of the ¹¹¹In-panitumumab in both non-tumour-bearing and A431 tumour-bearing mice. Tumour targeting was also visualized by γ-scintigraphy.

Conclusions and implications:

Panitumumab can be efficiently radiolabelled with ¹¹¹In with high labelling yields. Based on the efficiency in tumour targeting and low normal tissue uptake, panitumumab may be an effective targeting component for radioimmunodiagnostic and radioimmunotherapeutic applications.     

Genetic factors in non‐syndromic congenital heart malformations

Wessels MW, Willems PJ. Genetic factors in non‐syndromic congenital heart malformations. The genetic defect in most patients with non‐syndromic congenital heart malformations (CHM) is unknown, although more than 40 different genes have already been implicated. Only a minority of CHM seems to be due to monogenetic mutations, and the majority occurs sporadically. The multifactorial inheritance hypothesis of common diseases suggesting that the cumulative effect of multiple genetic and environmental risk factors leads to disease, might also apply for CHM. We review here the monogenic disease genes with high‐penetrance mutations, susceptibility genes with reduced‐penetrance mutations, and somatic mutations implicated in non‐syndromic CHM.     

Nail psoriasis in Germany: epidemiology and burden of disease

Background Although nail psoriasis affects a marked proportion of patients with psoriasis and causes significant psychological stress, only few epidemiological data characterizing patients with nail involvement are available. Objectives To gain robust data on the epidemiology and disease burden of nail psoriasis in Germany. Methods Two nationwide, noninterventional, cross‐sectional studies on psoriasis health care were conducted in 2005 and 2007, involving 48 (2005) and 130 (2007) German office‐based and clinic‐based dermatological centres. Data of n = 3531 patients with psoriasis were collected using standardized questionnaires and physical examinations by trained dermatologists. Patients with nail psoriasis were compared with patients without any nail involvement concerning sex, age, disease duration, family history, disease severity, presence of psoriatic arthritis (PsA), health‐related quality of life (HRQoL), number of inpatient therapies, and days off work. Results Nail psoriasis was diagnosed in 40·9% of the patients; prevalence was 11·2 percentage points higher in men than in women. Patients with nail involvement had a longer disease duration (21·9 vs. 18·1 years), higher disease severity (mean Psoriasis Area and Severity Index 12·7 vs. 9·3), higher frequency of PsA (26·0% vs. 12·7%), stronger impairment of HRQoL (mean Dermatology Life Quality Index 8·9 vs. 7·3), and a 2·5‐fold higher rate of inpatient treatments. Conclusions Nail involvement is a relevant manifestation of psoriasis and is associated with a higher disease severity and quality of life impairment. Accordingly, management of psoriasis should include a special focus on nail involvement.     

Longitudinal follow-up examination of antigliadin antibody positive children and adults

BACKGROUND: We previously investigated the prevalence of asymptomatic celiac disease in 3004 healthy children and 4313 adult blood donors by screening for IgA and IgG class antigliadin antibodies (AGA) and IgA class anti-endomysial antibodies (EmA). In none of the 162 exclusive AGA-positive adults and in only one of the 117 exclusive AGA-positive children could celiac disease be diagnosed. We followed up AGA-positive individuals in respect of the significance of the AGA. METHODS: All AGA-positive children and adults were invited for a follow-up clinical examination and laboratory investigations including AGA-IgA, AGA-IgG and EmA. Celiac disease-specific antibodies were also determined in stool samples. RESULTS: Sixty-nine adults and 47 children returned for follow-up. In 26 (37.7%) cases of the 69 adults formerly tested AGA-positive, AGA were still detectable after an average period of 3.7 years. In 21 (44.7%) cases of 47 formerly AGA-positive children, AGA were still detectable after an average period of 4.3 years. None of the 69 adults and 47 children showed seroconversion to EmA. There were no significant abnormalities in the laboratory results or any clinical signs of enteropathy.The appearance of fecal and serum antibodies was compared in 112 subjects but no correlation between fecal and serum antigliadin antibodies was found. CONCLUSIONS: In both studied populations of adults and children, AGA disappeared in more than 50% of the cases. The appearance of AGA has to be interpreted as a non-specific immunomodulation phenomenon, confirming the low specificity of AGA as a serologic marker for celiac disease.