Acute pulmonary histoplasmosis as an imported disease

A previously healthy 44-year-old male traveller presented with a dry cough, fever and an abnormal chest X-ray after a stay in Guatemala, where he had explored bat caves. Acute pulmonary histoplasmosis was diagnosed after culture of Histoplasma capsulatum from bronchial washings. A favourable response was seen upon treatment with itraconazole for six weeks. Acute pulmonary histoplasmosis should be considered in a healthy traveller returning with fever from the USA or subtropical areas.     

Hyperlipoproteinemia enhances susceptibility to acute disseminated Candida albicans infection in low-density-lipoprotein-receptor-deficient mice

Recent studies have suggested the use of lipoproteins as an adjuvant treatment of lethal gram-negative infections. However, other important microorganisms for the etiology of sepsis, such as Candida species, grow better in lipid-rich environments. We investigated the effect of hyperlipoproteinemia on systemic candidiasis in low-density-lipoprotein-receptor-deficient (LDLR-/-) mice, in which the loss of the receptor results in a seven- to ninefold-higher plasma LDL level than that in their wild-type littermates (C57BL/6J). LDLR-/- mice died earlier, and the outgrowth of Candida albicans in the kidneys and livers of LDLR-/- mice was significantly higher compared with that of controls. After infection, circulating cytokine concentrations were significantly higher in LDLR-/- mice. In vitro, C. albicans grew better in plasma samples of LDLR-/- mice than in control plasma samples and peritoneal macrophages of LDLR-/- mice challenged with heat-killed C. albicans produced more cytokines than did those of controls. This latter phenomenon was probably due to increased binding of yeast cells to macrophages of LDLR-/- mice. These data suggest that hyperlipoproteinemia is deleterious in systemic candidiasis.     

Delay in administering the first dose of antibiotics in patients admitted to hospital with serious infections

A 66-year old female was admitted to our ICU in septic shock with accompanying signs of gastroenteritis and diabetic-related hyperglycemia. Computer tomography of the abdomen revealed the rare diagnosis of emphysematous pyelonephritis. Immediate nephrectomy led to a favourable outcome in this dramatic case. Although abscess drainage and broad-based antibiotic therapy are generally the first-line therapy today, emergency surgery would seem to be indicated in selected cases.     

Nitrogen concentration and nitrate/ammonium ratio affect yield and change the oxalic acid concentration and fatty acid profile of purslane (Portulaca oleracea L.) grown in a soilless culture system

Purslane is an excellent source of omega‐3 fatty acids, amino acids and vitamins. The aim of this research was to study the effect of different nitrogen levels and NO₃⁻‐N/NH₄⁺‐N ratios in the nutrient solution on the yield and on the oxalic acid content and fatty acid profile in purslane grown in a soilless culture system. Two experiments were carried out to test different levels of nitrogen: (1) 8–12–16 mmol L⁻¹ and (2) 0–12–24–36 mmol L⁻¹. A third experiment was carried out maintaining the N level fixed (12 mmol L⁻¹) but varying the NO₃⁻‐N/NH₄⁺‐N ratio: 60:40, 40:60, 0:100. The results indicated that plants grew with increasing nitrogen level up to 36 mmol L⁻¹. Nitrogen supplied in both NO₃⁻ and NH₄⁺ forms produced bigger plants than N supplied in NH₄⁺ form only. Nitrogen did not significantly influence the polyunsaturated fatty acid content in the canopy. Significant trends were found for α‐linolenic acid (LNA; 18:3 n‐3) and linoleic acid (LA; 18:2 n‐6), indicating a favorable accumulation of omega‐3 fatty acids with increasing N; palmitic acid decreased by increasing N and by switching the NO₃⁻/NH₄⁺ ratio towards the NH₄⁺ level in the nutrient solution, but using 0:100 NO₃⁻/NH₄⁺, decreased plant quality. Increasing N lowered oxalic acid production and palmitic acid content, enhancing purslane nutritional quality. Keeping a high N level in the nutrient solution with a 40:60 NO₃⁻/NH₄⁺ ratio would give the best results in terms of yield, oxalic acid concentration and fatty acid profile. Copyright © 2006 Society of Chemical Industry     

Fc epsilonRI-deficient mice infected with Schistosoma mansoni mount normal Th2-type responses while displaying enhanced liver pathology

The IgE/Fc epsilonRI interaction is postulated to play an important role in resistance to helminths both at the level of anti-parasitic effector cell function and in the initiation of Th2 responses through IL-4 produced by Fc epsilonRI+ non-B, non-T (NBNT) cells. To formally evaluate the role of IgE/Fc epsilonRI signaling in the host response to helminths we studied Schistosoma mansoni infection in Fc epsilonRI knockout (KO) mice. Infected wild-type (wt) and KO animals showed comparable adult worm and tissue egg burdens, arguing against a role for Fc epsilonRI interactions in host resistance. Significantly, NBNT cells from infected KO, in contrast to wt animals, did not secrete IL-4 when stimulated with anti-IgE Ab or soluble parasite Ag. Nevertheless, serum IgE levels and Th2 cytokine production profiles were comparable in both strains of mice, demonstrating that the Ag-dependent stimulation of IL-4 secretion by NBNT cells is not essential for helminth-induced Th2 differentiation. However, when stimulated with low Ag doses, splenocytes from infected Fc epsilonRI-deficient mice produced less IL-4 in vitro than similar cultures from infected wt animals, an effect attributable to their defective NBNT cell function. Moreover, infected KO mice showed enhanced egg granuloma formation and hepatic fibrosis, revealing that the IgE/Fc epsilonRI interaction, while not essential for Th2 response development or resistance to primary infection, plays a significant role in down-regulating host pathology.     

Bacterial lipopolysaccharide binds and stimulates cytokine-producing cells before neutralization by endogenous lipoproteins can occur

Lipoproteins are able to bind to lipopolysaccharide (LPS) and neutralize its deleterious effects. However, it is not clear why the LPS-binding capacity of circulating lipoproteins, which is 10- to 10 000-fold above the maximal LPS concentrations found in septic patients, is not sufficient to inhibit the effects of LPS during an infection, whereas infusion of exogenous lipoproteins has a potent inhibitory action. In this study, the kinetics of LPS-neutralization by VLDL, LDL, and HDL were investigated, at lipoprotein-to-LPS ratios found in severe Gram-negative sepsis. At least 4-8-h preincubation of LPS with either LDL or HDL were necessary to inhibit 50% of the LPS-induced TNF-alpha production by human peripheral blood mononuclear cells (PBMC), whereas after 24 h of preincubation LDL or HDL strongly inhibited the TNF-alpha synthesis (70-90%, P<0.01). VLDL was the least effective lipoprotein fraction. In contrast, FITC-LPS bound to PBMC much more rapidly, with 70% of the total binding after 30 min, and 90% after 1-h incubation. The increase of LDL or HDL concentrations up to 10-fold (as in experimental models of hyperlipoproteinaemia) was able not only to further decrease TNF-alpha production after long LPS-lipoproteins preincubation periods, but also to improve the kinetics of LPS neutralization. In conclusion, LPS binds and stimulates the mononuclear cells in circulation before neutralization by endogenous lipoproteins can occur. Additional increase in the lipoprotein-to-LPS molar ratio (e.g. by infusion of exogenous lipoproteins) accelerates the kinetics of LPS neutralization, and may be useful as adjunctive therapy in severe Gram-negative infections.     

Helicobacter hepaticus triggers colitis in specific-pathogen-free interleukin-10 (IL-10)-deficient mice through an IL-12- and gamma interferon-dependent mechanism

Mice rendered deficient in interleukin-10 (IL-10) by gene targeting (IL-10(-/-) mice) develop chronic enterocolitis resembling human inflammatory bowel disease (IBD) when maintained in conventional animal facilities. However, they display a minimal and delayed intestinal inflammatory response when reared under specific-pathogen-free (SPF) conditions, suggesting the involvement of a microbial component in pathogenesis. We show here that experimental infection with a single bacterial agent, Helicobacter hepaticus, induces chronic colitis in SPF-reared IL-10(-/-) mice and that the disease is accompanied by a type 1 cytokine response (gamma interferon [IFN-gamma], tumor necrosis factor alpha, and nitric oxide) detected by restimulation of spleen and mesenteric lymph node cells with a soluble H. hepaticus antigen (Ag) preparation. In contrast, wild-type (WT) animals infected with the same bacteria did not develop disease and produced IL-10 as the dominant cytokine in response to Helicobacter Ag. Strong H. hepaticus-reactive antibody responses as measured by Ag-specific total immunoglobulin G (IgG), IgG1, IgG2a, IgG2b, IgG3, and IgA were observed in both WT and IL-10(-/-) mice. In vivo neutralization of IFN-gamma or IL-12 resulted in a significant reduction of intestinal inflammation in H. hepaticus-infected IL-10(-/-) mice, suggesting an important role for these cytokines in the development of colitis in the model. Taken together, these microbial reconstitution experiments formally establish that a defined bacterial agent can serve as the immunological target in the development of large bowel inflammation in IL-10(-/-) mice and argue that in nonimmunocompromised hosts IL-10 stimulated in response to intestinal flora is important in preventing IBD.     

Consumers' Responses to Choice-based Letting Mechanisms

During the 1990s a large majority of the social rented sector managers in the Netherlands shifted towards an advert model of allocation in place of a waiting list system. This paper focuses on the consumer's response to this new letting mechanism. Three case studies were conducted, geared to evaluate consumers' appreciation and understanding of the advert model. Various additional local, regional or national evaluations are used to put the findings from the case studies in perspective. Generally, the public appreciates the advert model more than the distribution system. However, insufficient understanding of the complex do-it-yourself allocation system affects appreciation of the system and access to vacancies both negatively. On average, people on low income and ethnic minority members (overlapping groups) were more prone to lack of understanding and were less successful applicants as a result. Moreover, the allocation mechanism has not changed differences in resources and bargaining power and its effects on the outcome of the allocation process.     

The Structural Chemistry of Metallocorroles: Combined X-ray Crystallography and Quantum Chemistry Studies Afford Unique Insights

Although they share some superficial structural similarities with porphyrins, corroles, trianionic ligands with contracted cores, give rise to fundamentally different transition metal complexes in comparison with the dianionic porphyrins. Many metallocorroles are formally high-valent, although a good fraction of them are also noninnocent, with significant corrole radical character. These electronic-structural characteristics result in a variety of fascinating spectroscopic behavior, including highly characteristic, paramagnetically shifted NMR spectra and textbook cases of charge-transfer spectra. Although our early research on corroles focused on spectroscopy, we soon learned that the geometric structures of metallocorroles provide a fascinating window into their electronic-structural characteristics. Thus, we used X-ray structure determinations and quantum chemical studies, chiefly using DFT, to obtain a comprehensive understanding of metallocorrole geometric and electronic structures. This Account describes our studies of the structural chemistry of metallocorroles. At first blush, the planar or mildly domed structure of metallocorroles might appear somewhat uninteresting particularly when compared to metalloporphyrins. Metalloporphyrins, especially sterically hindered ones, are routinely ruffled or saddled, but the missing meso carbon apparently makes the corrole skeleton much more resistant to nonplanar distortions. Ruffling, where the pyrrole rings are alternately twisted about the M-N bonds, is energetically impossible for metallocorroles. Saddling is also uncommon; thus, a number of sterically hindered, fully substituted metallocorroles exhibit almost perfectly planar macrocycle cores. Against this backdrop, copper corroles stand out as an important exception. As a result of an energetically favorable Cu(d(x2-y2))-corrole(π) orbital interaction, copper corroles, even sterically unhindered ones, are inherently saddled. Sterically hindered substituents accentuate this effect, sometimes dramatically. Thus, a crystal structure of a copper β-octakis(trifluoromethyl)-meso-triarylcorrole complex exhibits nearly orthogonal, adjacent pyrrole rings. Intriguingly, the formally isoelectronic silver and gold corroles are much less saddled than their copper congeners because the high orbital energy of the valence d(x2-y2) orbital discourages overlap with the corrole π orbital. A crystal structure of a gold β-octakis(trifluoromethyl)-meso-triarylcorrole complex exhibits a perfectly planar corrole core, which translates to a difference of 85° in the saddling dihedral angles between analogous copper and gold complexes. Gratifyingly, electrochemical, spectroscopic, and quantum chemical studies provide a coherent, theoretical underpinning for these fascinating structural phenomena. With the development of facile one-pot syntheses of corrole macrocycles in the last 10-15 years, corroles are now almost as readily accessible as porphyrins. Like porphyrins, corroles are promising building blocks for supramolecular constructs such as liquid crystals and metal-organic frameworks. However, because of their symmetry properties, corrole-based supramolecular constructs will probably differ substantially from porphyrin-based ones. We are particularly interested in exploiting the inherently saddled, chiral architectures of copper corroles to create novel oriented materials such as chiral liquid crystals. We trust that the fundamental structural principles uncovered in this Account will prove useful as we explore these fascinating avenues.     

Decreased axosomatic input to motoneurons and astrogliosis in the spinal cord of aged rats

An increasing body of evidence indicates that aging-related impairments of nervous functions are caused by damage to neuron integrity rather than by loss of neurons. By using electron microscopy, we have examined axosomatic boutons on spinal cord motoneurons derived from aged and young adult Sprague-Dawley rats. The main finding was that about half of the examined motoneuron somata from aged rats had a reduced (50%) bouton coverage, which seemed to be caused by a smaller number of axosomatic bouton profiles. Long stretches of the cell body plasma membrane were apposed by pale processes, and immunolabeling for glial fibrillary acidic protein (GFAP) disclosed that a number of the aged motoneurons appeared embedded in GFAP immunopositive processes. Lumbar motoneurons seemed to be more severely affected than cervical motoneurons. At the ultrastructural level, affected motoneurons disclosed plasma membrane irregularities with appendages/sprout-like extensions that in some cases were sites for axosomatic contacts.