[Guidelines for the Management of Community Acquired Pneumonia in Children and Adolescents (Pediatric Community Acquired Pneumonia, pCAP) - Issued under the Responsibility of the German Society for Pediatric Infectious Diseases (DGPI) and the German Society for Pediatric Pulmonology (GPP)]. / S2k-Leitlinie Management der ambulant erworbenen Pneumonie bei Kindern und Jugendlichen (pädiatrische ambulant erworbene Pneumonie, pCAP).

The present guideline aims to improve the evidence-based management of children and adolescents with pediatric community-acquired pneumonia (pCAP). Despite a prevalence of approx. 300 cases per 100 000 children per year in Central Europe, mortality is very low. Prevention includes infection control measures and comprehensive immunization. The diagnosis can and should be established clinically by history, physical examination and pulse oximetry, with fever and tachypnea as cardinal features. Additional signs or symptoms such as severely compromised general condition, poor feeding, dehydration, altered consciousness or seizures discriminate subjects with severe pCAP from those with non-severe pCAP. Within an age-dependent spectrum of infectious agents, bacterial etiology cannot be reliably differentiated from viral or mixed infections by currently available biomarkers. Most children and adolescents with non-severe pCAP and oxygen saturation > 92 % can be managed as outpatients without laboratory/microbiology workup or imaging. Anti-infective agents are not generally indicated and can be safely withheld especially in children of young age, with wheeze or other indices suggesting a viral origin. For calculated antibiotic therapy, aminopenicillins are the preferred drug class with comparable efficacy of oral (amoxicillin) and intravenous administration (ampicillin). Follow-up evaluation after 48 - 72 hours is mandatory for the assessment of clinical course, treatment success and potential complications such as parapneumonic pleural effusion or empyema, which may necessitate alternative or add-on therapy.

Abituzumab combined with cetuximab plus irinotecan versus cetuximab plus irinotecan alone for patients with KRAS wild-type metastatic colorectal cancer: the randomised phase I/II POSEIDON trial.

BACKGROUND: Integrins are involved in tumour progression and metastasis, and differentially expressed on colorectal cancer (CRC) cells. Abituzumab (EMD 525797), a humanised monoclonal antibody targeting integrin αν heterodimers, has demonstrated preclinical activity. This trial was designed to assess the tolerability of different doses of abituzumab in combination with cetuximab and irinotecan (phase I) and explore the efficacy and tolerability of the combination versus that of cetuximab and irinotecan in patients with metastatic CRC (mCRC) (phase II part). METHODS: Eligible patients had KRAS (exon 2) wild-type mCRC and had received prior oxaliplatin-containing therapy. The trial comprised an initial safety run-in using abituzumab doses up to 1000 mg combined with a standard of care (SoC: cetuximab plus irinotecan) and a phase II part in which patients were randomised 1 : 1 : 1 to receive abituzumab 500 mg (arm A) or 1000 mg (arm B) every 2 weeks combined with SoC, or SoC alone (arm C). The primary end point was investigator-assessed progression-free survival (PFS). Secondary end points included overall survival (OS), response rate (RR) and tolerability. Associations between tumour integrin expression and outcomes were also assessed. RESULTS: Phase I showed that abituzumab doses up to 1000 mg were well tolerated in combination with SoC. Seventy-three (arm A), 71 (arm B) and 72 (arm C) patients were randomised to the phase II part. Baseline characteristics were balanced. PFS was similar in the three arms: arm A versus SoC, hazard ratio (HR) 1.13 [95% confidence interval (CI) 0.78-1.64]; arm B versus SoC, HR 1.11 (95% CI 0.77-1.61). RRs were also similar. A trend toward improved OS was observed: arm A versus SoC, HR 0.83 (95% CI 0.54-1.28); arm B versus SoC, HR 0.80 (95% CI 0.52-1.25). Grade ≥3 treatment-emergent adverse events were observed in 72%, 78% and 67% of patients. High tumour integrin αvß6 expression was associated with longer OS in arms A [HR 0.55 (0.30-1.00)] and B [HR 0.41 (0.21-0.81)] than in arm C. CONCLUSION: The primary PFS end point was not met, although predefined exploratory biomarker analyses identified subgroups of patients in whom abituzumab may have benefit. The tolerability of abituzumab combined with cetuximab and irinotecan was acceptable. Further study is warranted. CLINICALTRIALS.GOV IDENTIFIER: NCT01008475.

Febrile ulceronecrotic Mucha-Habermann disease following suspected hemorrhagic chickenpox infection in a 20-month-old boy.

We present the youngest pediatric patient so far with febrile ulcerative Mucha-Haberman disease (FUMHD) after an admitting clinical picture of hemorrhagic varicella infection. With a time to diagnosis of 25 days, the 20-month-old boy responded to low dose cyclosporine and prednisolone given for 3 months and is free of disease after 4 years of follow up. We describe a polyclonal CD8+ T cell response with elevated pro-inflammatory cytokines and a fivefold upregulation of the high-affinity Fc receptor type I (CD64) on granulocytes. Early consideration of FUMHD in the differential diagnosis of a systemic inflammatory disease combined with a generalized necrotizing rash is important for early and adequate management of children with this rare and challenging disease.

Prevalence of self reported food allergy in US adults: 2001, 2006, and 2010.

BACKGROUND: Epidemiologic evidence indicates that food allergies are increasing in the population. Information on a change in self-reported food allergy (srFA) in adults over time is lacking. OBJECTIVE: To report the prevalence of srFA and compare differences at three time points over a decade. METHODS: We analyzed srFA and reported physician-diagnosed food allergy in 4000 U.S. adults who participated in the 2010 U.S. Food and Drug Administration Food Safety Survey. Information on causative food(s), reaction severity characteristics, and various diagnostic factors was also analyzed. We compared 2010 Food Safety Survey data with 2006 and 2001 data, and highlighted relevant differences. RESULTS: SrFA prevalence increased significantly, to 13% in 2010 and 14.9% in 2006 compared with 9.1% in 2001 (p less than 0.001). Physician diagnosed food allergy was 6.5% in 2010, which was not significantly different compared with 7.6% in 2006 and 5.3% in 2001. SrFA increased in both men and women, non-Hispanic white and black adults, 50-59 year olds, and in adults with a high school or lower education. In 2010, milk, shellfish, and fruits were the most commonly reported food allergens, similar to 2001. Also, in 2010, 15% of reactions reportedly required a hospital visit and 8.4% were treated with epinephrine. Minor differences in reaction severity characteristics were noted among the surveys. CONCLUSIONS: Analysis of survey results indicates that the prevalence of srFA increased among U.S. adults from 2001 to 2010 and that adults are increasingly self-reporting FAs without obtaining medical diagnosis. Improved education about food allergies is needed for this risk group.

Supramolecular structure of polymorphic collagen fibrils.

Reconstituted cartilage collagen fibrils with an oblique banding pattern or with two types of symmetrical patterns, and reconstituted rattail tendon fibrils with a third type of symmetrical pattern were examined by electron microscopy and found to consist of narrow subfibrils having native-type cross-striations. Analysis of the four types of patterns by a graphic method of specific band matching revealed the orientation and axial relation of individual subfibrils and their component molecules. In fibrils with an oblique pattern, subfibrils have the same orientation and a regular 100A axial displacement. Observations on staining characteristics, folded fibrils, and transverse sections of embedded fibrils suggest that the obliquely banded fibrils are ribbonlike or layered structures. In the three types of fibrils with a symmetrical pattern, adjacent subfibrils are oppositely oriented and aligned within a 119-A segment of the 670-A major period. Considered together, the observations suggest that interaction sites on the surface of subfibrils (and perhaps on the surface of native collagen fibrils) occur in various patterns that are manifested accouding to the nature of the environment during fibril formation, and that such patterns can be mapped on the surface of subfibrils by noting the arrangement of subfibrils in polymorphic forms.

A symmetrical, extracellular fibril.

Symmetrical, extracellular fibrils, which are related to the "special fibrils" of the dermis described by Palade and Farquhar, have been found along the outer surface of the basement membrane covering the notochord in the tail of Rana catesbeiana (bullfrog) tadpoles. The fibrils are approximately 7,500 A long and occur singly or in clusters. The single fibrils are characterized by a symmetrical transverse band pattern and by attachment at both ends to the basement membrane. The clusters are various complex configurations which seemingly represent symmetrical fibrils in different states of aggregation. Symmetrical fibrils also occur in the skin of the tadpole tail and in the skin of the toad, Bufo marinus. It is proposed that a narrow, symmetrical fibril is the fundamental "special fibril."

Structural modulations of plasmalemmal vesicles.

Structural modulations affecting a small fraction of the population of plasmalemmal vesicles of vascular endothelia are described. They include forms which are apparently produced by the fusion of the vesicular membrane with the plasmalemma and by the successive elimination of the layers of the two fused membranes. Such modulations are assumed to represent stages in the discharge process of vesicular contents. Other forms, characterized by their flask shape and elongated neck, are assumed to represent stages in the formation and loading of membrane invaginations, followed by their being pinched off to form isolated vesicles. Stages in a membrane-fusion process leading to the formation of apertured fenestrae and channels are also described in fenestrated endothelia. The visualization of these structural details is greatly facilitated by staining tissue specimens with uranyl acetate before dehydration.

Studies on blood capillaries. I. General organization of blood capillaries in muscle.

THE WALL OF THE BLOOD CAPILLARIES OF SKELETAL MUSCLES (DIAPHRAGM, TONGUE, HIND LEGS) AND MYOCARDIUM OF THE RAT, GUINEA PIG, AND HAMSTER CONSISTS OF THREE CONSECUTIVE LAYERS OR TUNICS: the endothelium (inner layer), the basement membrane with its associated pericytes (middle layer), and the adventitia (outer layer). The flattened cells of the endothelium have a characteristic, large population of cytoplasmic vesicles which, within the attenuated periphery of the cells, may attain a maximum frequency of 120/micro(2) of cell front and occupy approximately 18% of the cytoplasmic volume; these values decrease as the cells thicken toward the perikaryon. The vesicles are 650-750 A in over-all diameter and are bounded by typical unit membranes. They occur as single units or are fused to form short chains of two to three vesicles. Each configuration may lie entirely within the cytoplasm or open onto the cell surface. In the latter case, the unit membrane of the vesicle is continuous, layer by layer, with the plasmalemma. Chains of vesicles opening simultaneously on both the blood and tissue fronts of the endothelial tunic have not been observed either in sections or in a tridimensional reconstruction of a sector of endothelial cell cytoplasm. Adjacent endothelial cells are closely apposed to one another and appear to be joined over a large part of their margins, possibly over their entire perimeter, by narrow belts of membrane fusion (zonulae occludentes). Except for tongue capillaries, patent intercellular gaps are rare or absent. The middle layer is formed by a continuous basement membrane ( approximately 500 A thick) and by pericytes which lie in between leaflets of this membrane. The tips of the pericyte pseudopodia penetrate through the inner leaflet of the basement membrane and join the endothelium in maculae occludentes. The adventitia is a discontinuous layer comprising cellular (macrophages, fibroblasts, mast cells) and extracellular (fibrils, amorphous matrix) elements. The same general type of construction appears to be used along the entire length of the capillary.

Studies on blood capillaries. II. Transport of ferritin molecules across the wall of muscle capillaries.

The pathway by which intravenously injected ferritin molecules move from the blood plasma across the capillary wall has been investigated in the muscle of the rat diaphragm. At 2 min after administration, the ferritin molecules are evenly distributed in high concentration in the blood plasma of capillaries and occur within vesicles along the blood front of the endothelium. At the 10-min time point, a small number of molecules appear in the adventitia, and by 60 min they are relatively numerous in the adventitia and in phagocytic vesicles and vacuoles of adventitial macrophages. Thereafter, the amount of ferritin in the adventitia and pericapillary regions gradually increases so that at 1 day the concentration in the extracellular spaces approaches that in the blood plasma. Macrophages and, to a lesser extent, fibroblasts contain large amounts of ferritin. 4 days after administration, ferritin appears to be cleared from the blood and from the capillary walls, but it still persists in the adventitial macrophages and fibroblasts. At all time points examined, ferritin molecules within the endothelial tunic were restricted to vesicles or to occasional multivesicular or dense bodies; they were not found in intercellular junctions or within the cytoplasmic matrix. Ferritin molecules did not accumulate within or against the basement membranes. Over the time period studied, the concentration of ferritin in the blood decreased, first rapidly, then slowly, in two apparently exponential phases. Liver and spleen removed large amounts of ferritin from the blood. Diaphragms fixed at time points from 10 min to 1 day, stained for iron by the Prussian Blue method, and prepared as cleared whole mounts, showed a progressive and even accumulation of ferritin in adventitial macrophages along the entire capillary network. These findings indicate: (1) that endothelial cell vesicles are the structural equivalent of the large pore system postulated in the pore theory of capillary permeability; (2) that the basement membrane is not a structural restraint in the movement of ferritin molecules across the capillary wall; (3) that transport of ferritin occurs uniformly along the entire length of the capillary; and (4) that the adventitial macrophages monitor the capillary filtrate and partially clear it of the tracer.

Biosynthesis of sulphated macromolecules by rabbit lens epithelium. II. Relationship to basement membrane formation.

Rabbit lens epithelial cells display a similar "cobblestone" morphology and produce the same complement of sulphated macromolecules (also see Heathcote, J.G., and R.W. Orkin, 1984, J. Cell Biol., 99:852-860) whether grown on plastic or glass, dried films of gelatin or type IV collagen with laminin, or on gels of type I collagen. There was no evidence of basement membrane formation by these cells when they were grown on plastic, glass, or dried films. In contrast, cultures that had been grown on gels deposited a discrete basement membrane that followed the contours of the basal surfaces of the cells and in addition, they secreted amorphous basement membrane-like material that diffused into the interstices of the gel and associated with the collagen fibrils of the gel. A significant proportion (approximately 70%) of the heparan sulphate proteoglycan fraction that was secreted into the culture medium (fraction MI) when the cells were grown on plastic became associated with the cell-gel layer in the gel cultures. Further, when basement membrane was isolated by detergent extraction, greater than 90% of the 35S-labeled material present was in this heparan sulphate proteoglycan.

Type VI collagen in extracellular, 100-nm periodic filaments and fibrils: identification by immunoelectron microscopy.

Filaments and fibrils that exhibit a 100-nm axial periodicity and occur in the medium and in the deposited extracellular matrix of chicken embryo and human fibroblast cultures have been tentatively identified with type VI collagen on the basis of their similar structural characteristics (Bruns, R. R., 1984, J. Ultrastruct. Res., 89:136-145). Using indirect immunoelectron microscopy and specific monoclonal and polyclonal antibodies, we now report their positive identification with collagen VI and their distribution in fibroblast cultures and in tendon. Primary human foreskin fibroblast cultures, labeled with anti-type VI antibody and studied by fluorescence microscopy, showed a progressive increase in labeling and changes in distribution with time up to 8 d in culture. With immunoelectron microscopy and monoclonal antibodies to human type VI collagen followed by goat anti-mouse IgG coupled to colloidal gold, they showed in thin sections specific 100-nm periodic labeling on extracellular filaments and fibrils: one monoclonal antibody (3C4) attached to the band region and another (4B10) to the interband region of the filaments and fibrils. Rabbit antiserum to type VI collagen also localized on the band region, but the staining was less well defined. Control experiments with antibodies to fibronectin and to procollagen types I and III labeled other filaments and fibrils, but not those with a 100-nm period. Heavy metal-stained fibrils with the same periodic and structural characteristics also have been found in both adult rat tail tendon and embryonic chicken tendon subjected to prolonged incubation in culture medium or treatment with adenosine 5'-triphosphate at pH 4.6. We conclude that the 100-nm periodic filaments and fibrils represent the native aggregate form of type VI collagen. It is likely that banded fibrils of the same periodicity and appearance, reported by many observers over the years in a wide range of normal and pathological tissues, are at least in part, type VI collagen.

Cartilage collagen: a staggered substructure in reconstituted fibrils.

In contrast to the typical transverse banding pattern of native and reconstituted skin collagen fibrils, reconstituted fibrils of cartilage collagen have an oblique banding pattern that results from a regular axial shift (89 angstroms) of component "subfibrils." The 89-angstrom shift may be related to the major helix of the collagen molecule.

Human-mouse interspecies collagen I heterotrimer is functional during embryonic development of Mov13 mutant mouse embryos.

To investigate whether the human pro alpha 1(I) collagen chain could form an in vivo functional interspecies heterotrimer with the mouse pro alpha 2(I) collagen chain, we introduced the human COL1A1 gene into Mov13 mice which have a functional deletion of the endogenous COL1A1 gene. Transgenic mouse strains (HucI and HucII) carrying the human COL1A1 gene were first generated by microinjecting the COL1A1 gene into wild-type mouse embryos. Genetic evidence indicated that the transgene in the HucI strain was closely linked to the endogenous mouse COL1A1 gene and was X linked in the HucII transgenic strain. Northern (RNA) blot and S1 protection analyses showed that the transgene was expressed in the appropriate tissue-specific manner and as efficiently as the endogenous COL1A1 gene. HucII mice were crossed with Mov13 mice to transfer the human transgene into the mutant strain. Whereas homozygous Mov13 embryos die between days 13 and 14 of gestation, the presence of the transgene permitted apparently normal development of the mutant embryos to birth. This indicated that the mouse-human interspecies collagen I heterotrimer was functional in the animal. The rescue was, however, only partial, as all homozygotes died within 36 h after delivery, with signs of internal bleeding. This could have been due to a functional defect in the interspecies hybrid collagen. Extensive analysis failed to reveal any biochemical or morphological abnormalities of the collagen I molecules in Mov13-HucII embryos. This may indicate that there was a subtle functional defect of the interspecies hybrid protein which was not revealed by our analysis or that another gene has been mutated by the retroviral insertion in the Mov13 mutant strain.

Food-induced anaphylaxis and cofactors - data from the anaphylaxis registry.

Food allergens are frequent causes of anaphylaxis. In particular in children and adolescents they are the most frequent elicitors of severe allergic reactions, and in adults food allergens rank third behind insect venom and drugs. Since July 2006 severe allergic reactions from Germany, Austria, and Switzerland are collected in the anaphylaxis registry. Currently 78 hospitals and private practises are connected. From July 2006 until February 2009 1,156 severe allergic reactions were registered. Among children and adolescents (n = 187, age range from 3 months to 17 years) food allergens were the most frequent triggers, comprising 58% of cases. In the adult group (n = 968, 18 - 85 years) food allergens were in the third position (16.3%) behind insect venom and drugs. In children legumes (31%) and in particular peanuts were frequently responsible food allergens, followed by tree nuts (25%) with hazelnut being the most frequent elicitor. In adults fruits (13.4%) most often induced severe food-dependent anaphylaxis, but also animal products (12.2%); among these most frequently crustaceans and molluscs. Cofactors were often suspected in food-dependent anaphylaxis, namely in 39% of the adult group and in 14% of the pediatric group. In adults drugs (22%) and physical activity (10%) were reported to be the most frequent cofactors, in children physical activity was suspected in 8.7% and drugs in 2.6%. Concomitant diseases like atopic dermatitis, allergic asthma, or allergic rhinoconjunctivitis were reported in 78% of children and adolescents and in 67% of the adults. In conclusion, food-induced anaphylaxis, its cofactors and concomitant diseases are age-dependent. The data offers to identify risk factors of anaphylaxis.

Adenosine receptor interactions and anxiolytics.

[3H]-N6-cyclohexyladenosine and [3H]-1,3-diethyl-8-phenylxanthine label the A1 subtype of adenosine receptor in brain membranes. The affinities of methylxanthines in competing for A1 adenosine receptors parallel their potencies as locomotor stimulants. The adenosine agonist N6-(phenylisopropyl) adenosine is a potent locomotor depressant. Both diazepam and N6-(L-phenylisopropyl)adenosine cause locomotor stimulation in a narrow range of subdepressant doses. Combined stimulant doses of the two agents depress motor activity, as do larger doses of either one, given separately. Evidence supporting and against the hypothesis that some of the actions of benzodiazepines are mediated via the adenosine system is reviewed. A number of compounds interact with both systems, probably because of physico-chemical similarities between adenosine and diazepam. It is concluded that of the four classic actions of benzodiazepines, the sedative and muscle relaxant (but not anxiolytic or anticonvulsant) actions could possibly be mediated by adenosine.

[1,2,4]Triazolo[4,3-a]quinoxalin-4-amines: a new class of A1 receptor selective adenosine antagonists.

Several [1,2,4]triazolo[4,3-a]quinoxalines that were reported as antidepressants in the patent literature were found to possess moderate affinity for the adenosine A1 and A2 receptors. On the basis of structural parallels with adenine and adenosine, the N-cyclopentyl derivative was synthesized and found to have improved affinity and selectivity for the A1 receptor. In the N-cyclopentyl series, affinity was optimal with trifluoromethyl substitution at the 1-position, resulting in a compound (9) with 7.3 nM A1 affinity and 138-fold selectivity for the A1 receptor.

C2,N6-disubstituted adenosines: synthesis and structure-activity relationships.

Extracellular adenosine receptors have been divided into two major subtypes, called A1 and A2. Substitution of the adenosine molecule with appropriate groups at C2 or N6 is known to impart selectivity for the A2 receptor over the A1 receptor. In the present study, we investigated whether substitution at both C2 and N6 would have additive effects on the A2/A1 affinity ratio, thereby providing compounds with greater A2 selectivity than presently available agents. Disappointingly, additivity appeared to hold only when an A1-selective group was present at N6. For instance, 2-(phenylamino) substitution of the A1-selective agonist N6-cyclopentyladenosine resulted in a 70-fold shift in selectivity in favor of the A2 receptor, but the same substitution applied to the A2-selective agonist N6-[2-(3,5-dimethoxyphenyl)-2-(2-methylphenyl)ethyl]adenosine resulted in a 100-fold loss of affinity with no change in A2 selectivity.

Beta-proline analogues as agonists at the strychnine-sensitive glycine receptor.

3-Carboxy-3,4-dehydropyrrolidine was found to bind with affinity equal to that of glycine in a [3H]strychnine binding assay. Simple substitution of the 1-, 2-, 4-, or 5-position resulted in marked loss of affinity. A decline in affinity was also found upon enlargement, contraction, or saturation of the 5-membered ring. However, beta-proline and azetidine-3-carboxylic acid retained significant binding affinity. Despite its good affinity in [3H]strychnine binding, 3-carboxy-3,4-dehydropyrrolidine showed only weak agonist activity in intracellular recordings of cultured murine spinal cord neurons. This apparent lack of correlation between binding and functional results is discussed in light of the current models of the strychnine-sensitive glycine receptor.

N6-(arylalkyl)adenosines. Identification of N6-(9-fluorenylmethyl)adenosine as a highly potent agonist for the adenosine A2 receptor.

Several N6-(arylalkyl)adenosines related to N6-benzyladenosine were synthesized, and their A1 and A2 adenosine receptor binding affinities were determined. The annulated derivative N6-(1-naphthylmethyl)adenosine resulted in a very potent A2 agonist (A1 Ki = 24 nM, A2 Ki = 9.1 nM), whereas N6-(9-anthracenylmethyl)adenosine was virtually inactive (A1 Ki = 9,000 nM, A2 Ki = 29,000 nM). Interestingly, the structurally similar N6-(9-fluorenylmethyl)adenosine was the most potent A2 agonist reported to date, with a Ki of 4.9 nM in A2 binding and 5.1 nM in A1 binding. The homologues N6-9-fluorenyladenosine and N6-[2-(9-fluorenyl)ethyl]adenosine showed little or no activity at either adenosine receptor. Effects of these agents on heart rate and coronary flow in the isolated rat heart paralleled their A1 and A2 binding affinities, respectively. These data suggest that for high affinity at the A2 receptor a planar hydrophobic function at a certain distance and angle from the N6 nitrogen is required.

Evaluation and synthesis of aminohydroxyisoxazoles and pyrazoles as potential glycine agonists.

Except for structurally similar small amino acids, such as alanine, beta-alanine, and serine, compounds acting as glycine-receptor agonists are an unknown class of pharmacological agents. To investigate the potential of small, substituted heterocycles to act as glycine agonists, we have evaluated the similarities between glycine and a series of hydroxy- and amino-substituted pyrazoles and isoxazoles through complementary molecular modeling techniques. Using a "scorecard approach" to determine the overall similarity of projected agonist structures to glycine, we prioritized synthesis and subsequently prepared several novel derivatives. The biological activity of these compounds was compared to that of glycine by using a [3H]strychnine-mediated glycine receptor binding assay. Despite the close similarity in the calculated parameters when compared to glycine, no significant receptor-binding activity was observed for the targeted analogues. These results illustrate the structurally exacting nature of the glycine receptor.