Table-top interferometry on extreme time and wavelength scales.

Short-pulse metrology and dynamic studies in the extreme ultraviolet (XUV) spectral range greatly benefit from interferometric measurements. In this contribution a Michelson-type all-reflective split-and-delay autocorrelator operating in a quasi amplitude splitting mode is presented. The autocorrelator works under a grazing incidence angle in a broad spectral range (10 nm - 1 µm) providing collinear propagation of both pulse replicas and thus a constant phase difference across the beam profile. The compact instrument allows for XUV pulse autocorrelation measurements in the time domain with a single-digit attosecond precision and a useful scan length of about 1 ps enabling a decent resolution of E/ΔE = 2000 at 26.6 eV. Its performance for selected spectroscopic applications requiring moderate resolution at short wavelengths is demonstrated by characterizing a sharp electronic transition at 26.6 eV in Ar gas. The absorption of the 11th harmonic of a frequency-doubled Yb-fiber laser leads to the well-known 3s3p64p1P1 Fano resonance of Ar atoms. We benchmark our time-domain interferometry results with a high-resolution XUV grating spectrometer and find an excellent agreement. The common-path interferometer opens up new opportunities for short-wavelength femtosecond and attosecond pulse metrology and dynamic studies on extreme time scales in various research fields.

High energy redshifted and enhanced spectral broadening by molecular alignment.

We demonstrate an efficient approach for enhancing the spectral broadening of long laser pulses and for efficient frequency redshifting by exploiting the intrinsic temporal properties of molecular alignment inside a gas-filled hollow-core fiber (HCF). We find that laser-induced alignment with durations comparable to the characteristic rotational time scale TRotAlign enhances the efficiency of redshifted spectral broadening compared to noble gases. The applicability of this approach to Yb lasers with (few hundred femtoseconds) long pulse duration is illustrated, for which efficient broadening based on conventional Kerr nonlinearity is challenging to achieve. Furthermore, this approach proposes a practical solution for high energy broadband long-wavelength light sources, and it is attractive for many strong field applications.

[Evaluation and Utilization - Quality Management in a Paediatric University Outpatient Department]. / Evaluation und Inanspruchnahme - Qualitätssicherung in der pädiatrischen Ambulanz einer Universitätsklinik.

BACKGROUND: Based on an increasing number of outpatient treatments, an extensive demand planning is necessary to ensure the quality of medical care. University outpatient clinics are special parts of this sector and therefore it is necessary that a research demonstrates the nearly uninvestigated position of a paediatric outpatient clinic. PATIENTS: The research at the university hospital for children and adolescents in Leipzig started in 2009 to survey 2283 of in total 9391 patients and the physicians. METHODS: Sociodemographic data as well as economic and medical facts were determined by using questionnaires. In each case a questionnaire was answered by the children or their accompanying persons and a separate one was completed by the respective doctor. RESULTS: The results created a foundation, on the basis of patient volume per day and per daytime. Less than 20% of the children admitted to consult the clinic for their first time. The majority of patients visit them because of a letter of referral. Most of the patients (58%) were younger than 6 years old. Approximately 35% of patients did not come from the city region of Leipzig. CONCLUSION: The investigation evidenced the necessity of a day and night operating institution for children in the region of Leipzig as well as the high specialisation of the outpatient clinic. In need of further investigation is the cooperation between several physicians to find out if this lots of medical examination are necessary or if there took place overlapping.

[Interdisciplinary AWMF guideline for the diagnostics of primary immunodeficiency]. / Interdisziplinäre AWMF-Leitlinie zur Diagnostik von primären Immundefekten (S2k).

BACKGROUND: Primary immunodeficiencies are potentially life-threatening diseases. Over the last years, the clinical phenotype and the molecular basis of an increasing number of immunological defects have been characterized. However, in daily practice primary immunodeficiencies are still often diagnosed too late. Considering that an early diagnosis may reduce morbidity and mortality of affected patients, an interdisciplinary guideline for the diagnosis of primary immunodeficiencies was developed on behalf of the Arbeitsgemeinschaft Pädiatrische Immunologie (API) and the Deutsche Gesellschaft für Immunologie (DGfI). METHODS: The guideline is based on expert opinion and on knowledge from other guidelines and recommendations from Germany and other countries, supplemented by data from studies that support the postulated key messages (level of evidence III). With the contribution of 20 representatives, belonging to 14 different medical societies and associations, a consensus-based guideline with a representative group of developers and a structured consensus process was created (S2k). Under the moderation of a representative of the Association of the Scientific Medical Societies in Germany (AWMF) the nominal group process took place in April 2011. RESULTS: The postulated key messages were discussed and voted on following a structured consensus procedure. In particular, modified warning signs for primary immunodeficiencies were formulated and immunological emergency situations were defined.

A hospital based study on inter- and intragenotypic diversity of human rotavirus A VP4 and VP7 gene segments, Germany.

BACKGROUND: Efforts to reduce the impact of group A rotaviruses on human morbidity and mortality rely on oral immunisation with live attenuated or recombinant vaccines. A major challenge in immunisation is the vast inter- and intragenotypic diversity accomplished by circulating rotaviruses. OBJECTIVES: To monitor rotavirus inter- and intragenotypic diversity in hospitalised children. STUDY DESIGN: From January 2008 to December 2009 stool samples from 1994 paediatric in-patients suffering from diarrhoea were screened for rotavirus. Rotavirus G- and P-genotypes were determined by nucleotide sequencing and phylogenetic analysis was performed. RESULTS: Rotavirus A was detected in stool samples of 341 children, comprising G1P[8], G2P[4], G3P[8], G4P[8], G9P[8], as well as uncommon G12P[6] genotypes and mixed infections. Predominant strains shifted from G1P[8] and G9P[8] genotypes in the first season to G3P[8] and G4P[8] genotypes in the second season. The highest intragenotypic diversity was detected in G1 strains and consisted of co-circulating G1-Ic, G1-Id, G1-Ie and G1-II rotaviruses. The G2 analysis revealed different intragenotypic lineages: G2-IIa, G2-IIb and G2-IIc. Interestingly, the circulating G4-Ib rotaviruses were characterised by insertions of 3 or 6 additional coding nucleotides within variable region 4 of VP7. Whereas different G9-III VP7 gene segments were detected G3-Ia sequences were highly homologous. In the VP4 analysis P[8]-III gene segment predominated over P[4]-Vb, P[8]-I, P[8]-IV and P[6]-I. CONCLUSIONS: A remarkable rotavirus heterogeneity was detected in the limited local setting and time span. Continued monitoring and nucleotide sequencing is necessary to document possible effects of rising immunisation levels on intragenotypic rotavirus diversity.

Clinical and immunological overlap between autoimmune lymphoproliferative syndrome and common variable immunodeficiency.

Autoimmune lymphoproliferative syndrome (ALPS) is mainly caused by defects in the CD95 pathway. Raised CD3+TCRαß+CD4-CD8- double negative T cells and impaired T cell apoptosis are hallmarks of the disease. In contrast, the B cell compartment has been less well studied. We found an altered distribution of B cell subsets with raised transitional B cells and reduced marginal zone B cells, switched memory B cells and plasma blasts in most of 22 analyzed ALPS patients. Moreover, 5 out of 66 ALPS patients presented with low IgG and susceptibility to infection revealing a significant overlap between ALPS and common variable immunodeficiency (CVID). In patients presenting with lymphoproliferation, cytopenia, hypogammaglobulinemia and impaired B cell differentiation, serum biomarkers were helpful in addition to apoptosis tests for the identification of ALPS patients. Our observations may indicate a role for apoptosis defects in some diseases currently classified as CVID.

Lethal influenza B myocarditis in a child and review of the literature for pediatric age groups.

CASE PRESENTATION: We report on the case of a 5 year-old girl who developed fulminant myocarditis due to acute infection with influenza virus type B. Cardiac arrest occurred suddenly, resuscitation efforts were not successful, and the patient died of congestive heart failure 24 h after admission to the hospital. DIAGNOSIS: Lymphocytic infiltration of cardiac tissues and virologic studies confirmed the suspected diagnosis of acute viral myocarditis. CONCLUSION: In conclusion, influenza virus type B is one of the infective agents that can cause rapid and fatal myocarditis in previously healthy children. Early cardiac support may be the only option to prevent fatal outcome.

Twenty year follow up of a patient with a new de-novo NLRP3 mutation (S595G) and CINCA syndrome.

We report on a 22-year-old girl with a history of recurrent febrile episodes, chronic arthritis, urticarial rash, and neurological symptoms including right hemiparesis, internal hydrocephalus, mental retardation, progressive deafness, and visual impairment. Treatment starting at age 20 months, including different combinations of immunosuppressive and antiinflammatory drugs such as corticosteroids and anti-TNFalpha antibody, was unsuccessful. Four years ago, we found a heterozygous S595G mutation in the NLRP3 gene of this patient. This prompted us to introduce anakinra, which resulted in considerable improvement of the patient's complaints.

Efficacy of human rotavirus vaccine against rotavirus gastroenteritis during the first 2 years of life in European infants: randomised, double-blind controlled study.

BACKGROUND: We aimed to assess the efficacy of the oral live attenuated human rotavirus vaccine Rotarix (RIX4414) for prevention of rotavirus gastroenteritis in European infants during their first 2 years of life. METHODS: 3994 study participants were enrolled from six countries and were randomly assigned two oral doses of either RIX4414 (n=2646) or placebo (n=1348), which were coadministered with the first two doses of specific childhood vaccinations. Follow-up for gastroenteritis episodes was undertaken from 2 weeks post-dose two through the two consecutive rotavirus seasons following vaccinations (combined efficacy follow-up period; mean duration 17 months [SD 1.6]). Our primary endpoint was vaccine efficacy against rotavirus gastroenteritis of any severity during the first efficacy follow-up period (2 weeks post-dose two to the end of the first rotavirus season). Stool specimens obtained during gastroenteritis episodes were tested for rotavirus by ELISA and typed by RT-PCR. Episodes scoring 11 or greater on the 20-point Vesikari scale were classified as severe. Analysis was according to protocol. This study is registered with ClinicalTrials.gov, number NCT00140686 (eTrack102247). FINDINGS: 120 infants were excluded from the according-to-protocol analysis. During the first efficacy follow-up period (mean duration 5.7 months [SD 1.2]), 24 of 2572 infants allocated RIX4414 versus 94 of 1302 given placebo had rotavirus gastroenteritis episodes of any severity, resulting in a vaccine efficacy of 87.1% (95% CI 79.6-92.1; p<0.0001). For the combined efficacy follow-up period, vaccine efficacy against severe rotavirus gastroenteritis was 90.4% (85.1-94.1; p<0.0001), for admission owing to rotavirus gastroenteritis 96.0% (83.8-99.5; p<0.0001), and for rotavirus-related medical attention 83.8% (76.8-88.9; p<0.0001), and significant protection against severe rotavirus gastroenteritis by circulating G1, G2, G3, G4, and G9 rotavirus types was shown. INTERPRETATION: In a European setting, two doses of RIX4414 coadministered with childhood vaccines provided high protection against any and severe rotavirus gastroenteritis, with an overall reduction of admissions for gastroenteritis over two consecutive rotavirus epidemic seasons.

Plasminogen deficiency.

Plasminogen (plg) deficiency has been classified as (i) hypoplasminogenemia or 'true' type I plg deficiency, and (ii) dysplasminogenemia, also called type II plg deficiency. Both forms, severe hypoplasminogenemia and dysplasminogenemia, are not causally linked to venous thrombosis. Dysplasminogenemia does not lead to a specific clinical manifestation and probably represents only a polymorphic variation in the general population, mainly in Asian countries. Severe hypoplasminogenemia is associated with compromised extracellular fibrin clearance during wound healing, leading to pseudomembraneous (ligneous) lesions on affected mucous membranes (eye, middle ear, mouth, pharynx, duodenum, upper and lower respiratory tract and female genital tract). Ligneous conjunctivitis is by far the most common clinical manifestation. More than 12% of patients with severe hypoplasminogenemia exhibit congenital occlusive hydrocephalus. In milder cases of ligneous conjunctivitis, topical application of plg-containing eye drops, fresh frozen plasma, heparin, corticosteroids or certain immunosuppressive agents (such as azathioprine) may be more or less effective. Oral treatment with sex hormones was successful in two female patients with ligneous conjunctivitis. In severe cases with possibly life-threatening multi-organ involvement, true therapeutic options are not available at present. The plg-knockout mouse is a useful tool to study the many different properties of plg in a variety of settings, such as wound healing, tissue repair and tissue remodeling, virulence and invasiveness of certain bacteria in the human host, tumor growth and dissemination, as well as arteriosclerosis.

[Acrodermatitis enteropathica (AE) is caused by mutations in the zinc transporter gene SLC39A4]. / Acrodermatitis enteropathica (AE) wird durch Mutationen im Zink-Transportergen SLC39A4 verursacht.

BACKGROUND: Acrodermatitis enteropathica (AE) is an autosomal recessively inherited disease caused by a decreased intestinal zinc resorption and characterized by severe dermatitis (preferably hands, feet, mouth, genital region), chronic diarrhoea, retardation of growth and development, alopecia and increased proneness to infections. In 2002 it was shown that mutations in the zinc transporter gene SLC39A4 is the cause of AE. CASE REPORT: Here we report 4 patients with typical clinical signs since early childhood. Under regular substitution with zinc all patients are more or less free of symptoms. The first patient revealed compound-heterozygous missense/nonsense mutations (P200L/ W401X), the three other patients were homozygous for a mutation in intron 1 (c.192 + 19G > A) of the SLC39A4 gene. CONCLUSION: The diagnosis of hereditary acrodermatitis enteropathica can now easily be confirmed by mutation analysis of the SLC39A4 gene.

Decreased factor XIII activity during severe Henoch-Schoenlein purpura -- does it play a role?

BACKGROUND: In patients with Henoch-Schoenlein purpura (HSP), particularly with severe gastrointestinal symptoms, an associated decrease of plasma factor XIII has been observed. PATIENT: The authors report a case of HSP in a boy and describe the development of factor XIII activities throughout the course of the disease. Every relapse of severe gastrointestinal manifestation was associated with a decrease of factor XIII. No improvement was seen after treatment with prednisone. The symptoms resolved each time factor XIII concentrate was administered. With the return of factor XIII to normal values eight weeks after admission abdominal symptoms ceased. CONCLUSION: The documented course supports the hypothesis that factor XIII activity correlates well with the severity of abdominal symptoms. Measuring factor XIII activity helps to identify those patients with severe gastrointestinal manifestation who may benefit from substitution therapy.

[Rare case of an epidemiologically important tuberculosis in childhood]. / Seltener Fall einer epidemiologisch bedeutsamen Tuberkulose im Kindesalter.

BACKGROUND: Tuberculosis is an infectious disease which is nearly forgotten in Germany because of its low incidence. CASE REPORT: We report on a 14-year-old german girl who was disregarded when active case-finding of her uncle's active pulmonary tuberculosis was carried out three years before. As a result she herself developed a severe infectious pulmonary tuberculosis. The delay between onset of symptoms and diagnosis gives cause for concern and led to active tuberculosis in her brother and her girl friend as well. The lack of information about tuberculosis in population and delay of medical detection in this case led unnecessarily to the continuing chain of infection. CONCLUSIONS: This case report shows that there are severe infectious courses of tuberculosis even in childhood which might get epidemiologically important. For earlier diagnosis and successful interruption of chains of infection tuberculosis in the German population even today has to be taken into account. Case detection through contact investigation of adults is of great importance in childhood and adolescence.

[Viral infections in pediatric cancer patients]. / Diagnose und Therapie von Virusinfektionen bei Kindern und Jugendlichen mit neoplastischen Erkrankungen.

Children with cancer or stem cell transplantation (SCT) are at considerable risk to develop life threatening viral infections. Due to both underlying disease and immunosuppressive therapy lymphocyte number and function are low and the cellular immunity against viral infections is restricted or missing. As immunosuppressive treatment regimens and mismatched or T-cell-depleted stem cell products are being used increasingly, viral infections will become an even greater problem in the future. PCR-based methods have become an indispensable tool for early recognition, preemptive therapy, and monitoring therapeutic responses by qualitative and quantitative approaches. Assays are now available that allow for parallel screening of the 16 most common viral agents. Responses to antiviral therapy are often limited in immunocompromised patients and mainly depend on the time of their initiation. Most antiviral agents have a toxicity profile that may become clinically relevant and curtail antiviral therapy. New options for treatment are therefore warranted. For the next future, these may include the transfer of specific T-cells and other immunotherapeutic approaches. This article provides the recommendations of the Infectious Diseases Working Party of the German Society for Pediatric Hematology/Oncology (GPOH) and the German Society for Pediatric Infectious Diseases (DGPI) for diagnosis and treatment of viral infections in children with cancer or post HSCT. They are based on the results of clinical trials, case series and expert opinions using the evidence criteria set forth by the Infectious Diseases Society of America (IDSA).