SVEP1 plays a crucial role in epidermal differentiation

SVEP1 is a recently identified multidomain cell adhesion protein, homologous to the mouse polydom protein, which has been shown to mediate cell‐cell adhesion in an integrin‐dependent manner in osteogenic cells. In this study, we characterized SVEP1 function in the epidermis. SVEP1 was found by qRT‐PCR to be ubiquitously expressed in human tissues, including the skin. Confocal microscopy revealed that SVEP1 is normally mostly expressed in the cytoplasm of basal and suprabasal epidermal cells. Downregulation of SVEP1 expression in primary keratinocytes resulted in decreased expression of major epidermal differentiation markers. Similarly, SVEP1 downregulation was associated with disturbed differentiation and marked epidermal acanthosis in three‐dimensional skin equivalents. In contrast, the dispase assay failed to demonstrate significant differences in adhesion between keratinocytes expressing normal vs low levels of SVEP1. Homozygous Svep1 knockout mice were embryonic lethal. Thus, to assess the importance of SVEP1 for normal skin homoeostasis in vivo, we downregulated SVEP1 in zebrafish embryos with a Svep1‐specific splice morpholino. Scanning electron microscopy revealed a rugged epidermis with perturbed microridge formation in the centre of the keratinocytes of morphant larvae. Transmission electron microscopy analysis demonstrated abnormal epidermal cell‐cell adhesion with disadhesion between cells in Svep1‐deficient morphant larvae compared to controls. In summary, our results indicate that SVEP1 plays a critical role during epidermal differentiation.     

Bichat guidelines for the clinical management of brucellosis and bioterrorism-related brucellosis

Interest in Brucella species as a biological weapon stems from the fact that airborne transmission of the agent is possible. It is highly contagious and enters through mucous membranes such as the conjunctiva, oropharynx, respiratory tract and skin abrasions. It has been estimated that 10-100 organisms only are sufficient to constitute an infectious aerosol dose for humans. Signs and symptoms are similar in patients whatever the route of transmission and are mostly non-specific. Symptoms of patients infected by aerosol are indistinguishable from those of patients infected by other routes. Regimens containing doxycycline plus streptomycin or doxycycline plus rifampin are effective for most forms of brucellosis. Isolation of patients is not necessary. Trimethoprim-sulfamethoxazole and fluoroquinolones also have good results against Brucella, but are associated with high relapse rates when used as monotherapy. The combination of ofloxacin plus rifampicin is associated with good results. Even if there is little evidence to support its utility for post-exposure prophylaxis, doxycycline plus rifampicin is recommended for 3 to 6 weeks.     

Dynamic force spectroscopy of parallel individual Mucin1-antibody bonds

We used atomic force microscopy to measure the binding forces between Mucin1 (MUC1) peptide and a single-chain variable fragment (scFv) antibody selected from a scFv library screened against MUC1. This binding interaction is central to the design of molecules used for targeted delivery of radioimmunotherapeutic agents for prostate and breast cancer treatment. Our experiments separated the specific binding interaction from nonspecific interactions by tethering the antibody and MUC1 molecules to the atomic force microscope tip and sample surface with flexible polymer spacers. Rupture force magnitude and elastic characteristics of the spacers allowed identification of the rupture events corresponding to different numbers of interacting proteins. We used dynamic force spectroscopy to estimate the intermolecular potential widths and equivalent thermodynamic off rates for monovalent, bivalent, and trivalent interactions. Measured interaction potential parameters agree with the results of molecular docking simulation. Our results demonstrate that an increase of the interaction valency leads to a precipitous decline in the dissociation rate. Binding forces measured for monovalent and multivalent interactions match the predictions of a Markovian model for the strength of multiple uncorrelated bonds in a parallel configuration. Our approach is promising for comparison of the specific effects of molecular modifications as well as for determination of the best configuration of antibody-based multivalent targeting agents.     

Relation of N-terminal pro B-type natriuretic peptide to progression of aortic valve disease.

AIMS: Recently an elevation of B-type natriuretic peptide (BNP) and its N-terminal fragment (NT-proBNP) in patients with aortic stenosis (AS) and aortic regurgitation (AR) has been described. The objective of this study was to evaluate the relation of NT-proBNP values to the progression of aortic valve disease. METHODS AND RESULTS: One hundred and sixty-eight patients were included. NT-proBNP was elevated in patients with AS (n=109) and AR (n=37) linked to disease severity. Values for NT-proBNP, pressure gradient, and left ventricular mass were identical in patients (n=22) after previous valve replacement and in those patients with mild AS. NT-proBNP levels decreased in 86 patients after valve replacement (2292+/-353 vs. 785+/-101 pg/ml; P<0.01) but increased in 82 patients who were treated conservatively (616+/-120 vs. 1155+/-432 pg/mL; P=0.029), related to the progression of disease. CONCLUSION: NT-proBNP is elevated in patients with aortic valve disease linked to disease severity and decreases after successful surgical therapy but increases in conservatively treated patients. These data underline the consistent relation of NT-proBNP to severity of aortic valve disease. Therefore, NT-proBNP should be considered as a biomarker for the monitoring of disease during follow-up, but further studies are warranted.     

Orale Thrombozytenhemmung in der primären und sekundären Prävention

Cardiovascular disease is the leading cause of death in western societies, with further increasing incidence. Therefore both, primary and secondary prevention play a pivotal role. Medicamentous prevention schemes include the antithrombotic drugs acetylsalicylic acid (ASS) and clopidogrel. A number of studies tested the efficacy and safety of ASS for primary prevention. A meta-analysis of these primary prevention trials could demonstrate a decrease of cardiovascular events only for patients being at high cardiovascular risk. However, since ASS does not influence the mortality but is significantly increasing the risk for bleeding, careful risk stratification is indispensable prior to preventive chronic administration of the drug. Therapy with ASS in the secondary prevention is commonly accepted and clearly evidence-based given that a meta-analysis of 145 trials could demonstrate a significant decrease in mortality. A daily dose of 100 mg has been shown to achieve sufficient antithrombotic effects with an acceptable rate of side effects. Clopidogrel is currently not used for primary prevention, since evidence is lacking and the costs are high. For secondary prevention after acute coronary syndromes, a decrease of cardiovascular events could be demonstrated for clopidogrel. This benefit was especially pronounced after percutaneous coronary interventions. However, clopidogrel could not decrease the mortality. Therefore, long-term treatment with clopidogrel in the secondary prevention should be based on a critical appraisal of risk and benefit on the one hand and socioeconomic aspects on the other hand.     

AIDS-related B-cell lymphoma (ARL): correlation of prognosis with differentiation profiles assessed by immunophenotyping

This study was undertaken to analyze the differentiation profiles assessed by immunophenotyping in AIDS-related B-cell lymphoma (ARL) and their relation to the clinical course. Paraffin-embedded sections of 89 ARL cases during 1989 to 2004 were stained immunohistochemically with antibodies to CD3, CD10, CD20, CD38, CD138/Syndecan-1 (Syn-1), multiple myeloma-1/interferon regulatory factor-4 (MUM1/IRF4), B-cell lymphoma protein-2 (BCL-2), BCL-6, latent membrane protein-1 (LMP-1), and Ki-67. Expression of CD10 and CD20 were associated with better overall survival (OS; P = .009 and P = .04, respectively). Expression of CD20 was associated with longer disease-free survival (DFS; P = .03), whereas expression of CD138/Syn-1 was associated with shorter DFS (P = .03). OS and DFS were worse in patients with immunophenotypic profiles related to post-germinal center (GC) differentiation (BCL-6 and CD10 negative, MUM1/IRF4 and/or CD138/Syn-1 positive) when compared with GC differentiation (P = .01). When controlled for age-adjusted International Prognostic Index (IPI), prior AIDS-defining illness (ADI), and year of ARL diagnosis, a post-GC differentiation remained significantly associated with poor OS and DFS. Expression of CD10 was associated with a preserved immunocompetence, whereas CD20 was less frequent in patients developing ARL while on highly active antiretroviral therapy (P = .04). In summary, lack of CD20 or CD10 expression and a post-germinal center signature are associated with a worse prognosis in ARL.     

Influenza A(H5N8) Virus Similar to Strain in Korea Causing Highly Pathogenic Avian Influenza in Germany

Highly pathogenic avian influenza (H5N8) virus, like the recently described H5N8 strain from Korea, was detected in November 2014 in farmed turkeys and in a healthy common teal (Anas crecca) in northeastern Germany. Infected wild birds possibly introduced this virus.     

Virologic and CD4+ cell responses to new nucleoside regimens: switching to stavudine or adding lamivudine after prolonged zidovudine treatment of human immunodeficiency virus infection. ACTG 302 Study Team. AIDS Clinical Trials Group

Clinical benefit of zidovudine alone in the treatment of HIV infection wanes after several years, with decreasing CD4+ cell numbers and increasing HIV RNA in plasma. To develop treatment strategies following prolonged zidovudine treatment, 92 subjects from the AIDS Clinical Trials Group (ACTG) 175 study after a median of 3.6 years of zidovudine monotherapy were randomized to treatment with stavudine or zidovudine and lamivudine. Evaluation of long-term changes, the average of 40- and 48-week HIV plasma RNA, demonstrated that lamivudine and zidovudine provided significantly greater virologic suppression compared with stavudine (mean decrease 0.70 versus 0.18 1og10 copies/ml,p = 0.003). Twenty-nine percent of zidovudine plus lamivudine recipients had HIV RNA levels below 500 copies per milliliter at 48 weeks as compared with 4% of stavudine recipients (p = 0.02). Both regimens significantly increased CD4+ cell numbers, the means of weeks 40 and 48 rose to 49 and 36 CD4+ cells per cubic millimeter among zidovudine plus lamivudine and stavudine recipients, respectively. Treatments were well tolerated and only 3 of 92 subjects died or developed AIDS within 48 weeks. In zidovudine-experienced subjects, addition of lamivudine resulted in significantly decreased plasma HIV RNA levels at 48 weeks compared with treatment with stavudine alone.     

Chirurgische Therapie der Lungentuberkulose

Die Indikation zur Chirurgie der Lungentuberkulose ist heutzutage eine Individualindikation, die interdisziplinär erarbeitet werden muss. Der geeignete Operationszeitpunkt ist von entscheidender Bedeutung, da er über Erfolg, Verlauf und Heilung entscheidet. Als Indikationen zur chirurgischen Therapie gelten: