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Biomedical subjects

M Schaller

Publications and source records attributed to M Schaller.

At least 19 recordsLinked to original sources
PubMed2006

[Sandfly fever Naples virus (serotype Toscana) infection with meningeal involvement after a vacation in Italy].

HISTORY AND CLINICAL FINDINGS: A 69-year-old man was admitted to our hospital with severe headache, recurrent episodes of fever and deterioration of general health. He returned from a vacation in Tuscany (Italy) a few days before admission. Physical examination revealed slight nuchal rigidity and an elevated body temperature of 37.8 C but was otherwise unremarkable. INVESTIGATIONS: Differential blood count showed a lymphocytopenia. Other abnormal laboratory findings included an elevated blood sedimentation rate and a slightly increased C-reactive protein value. Abdominal sonography demonstrated a marginally enlarged spleen. DIAGNOSIS, TREATMENT AND CLINICAL COURSE: A lumbar puncture was performed. Cerebrospinal fluid analysis revealed a lymphocytic meningitis. Serological examination of a blood sample showed specific IgM-antibodies against sandfly fever Naples virus (SFNV), subtype Toscana virus (TOSV). After this diagnosis had been made initially instituted intravenous administration of antibiotics and antiviral medication were discontinued. The patient's symptoms improved rapidly under symptomatic treatment. Slight headaches without episodes of fever persisted for a few weeks without residual neurological symptoms. CONCLUSIONS: A history of travel should always be sought in patients with clinical signs for meningitis. Considering the increasing spread and incidence of SFNV and its subtype Toscana in mediterranean countries, such virus should be kept in mind when treating patients who present such symptoms after returning from those countries during the summer season.

Acyclovir↗
PubMed2005

The impact of skin viability on drug metabolism and permeation -- BSA toxicity on primary keratinocytes.

For testing cutaneous absorption of drugs, ingredients of cosmetics and also for risk assessment of industrial compounds predictable in vitro test protocols are under investigation using excised skin or reconstructed human epidermis. Since the metabolizing enzymes expressed by viable skin can influence the absorption behaviour of substances by changing their structure and thereby their physicochemical characteristics, the metabolic capacity should be considered in the design of the test protocols of compounds susceptible to metabolism. Then data, generated using viable reconstructed epidermis may reflect the in vivo situation. Interestingly, bovine serum albumin (BSA) commonly used in receptor media in permeation studies to facilitate solubility of highly lipophilic substances strongly inhibited the metabolism of topically applied prednicarbate in reconstructed epidermis. Here, we show that 5% BSA is toxic to reconstructed epidermis and keratinocytes which was consistent with the earlier findings. While media toxicity (deficiency media) was at least partly the cause of both apoptotic and necrotic processes in keratinocytes, BSA only slightly increased the rate of necrotic cells. Moreover, caspase inhibitors did not reduce BSA toxicity. Yet, the results show that BSA toxicity on keratinocytes has to be carefully considered if this protein is used in permeation studies with reconstructed epidermis.

Annexin A5↗
PubMed2005

Reconstructed epidermis versus human and animal skin in skin absorption studies.

European chemical policy in general and the REACH initiative in particular will increase the number of chemical substances submitted to toxicological evaluation by several orders of magnitude compared to the current status. To limit animal exposure the resulting enormous increase in testing, however, asks for validated in vitro test systems. While the OECD favours in vitro testing for cutaneous absorption using viable human and animal skin (Guideline 428) the availability of viable human skin is already limited today. We present a comparison of various in vitro techniques suitable for routine skin absorption studies including commercially available reconstructed human epidermis which may be a reliable alternative to excised human and animal skin. In order to develop a protocol for the subsequent transfer to partner laboratories the experimental set-up was analysed stepwise using the OECD reference compounds caffeine and testosterone. Franz cell type, the donor and receptor media for hydrophilic/lipophilic substances, albumin and tensid addition, and storage conditions of the excised skins were systematically varied. A protocol has been developed which now allows to proceed to the pre-validation process.

Administration, Topical↗
PubMed2005

Induction of a chemoattractive proinflammatory cytokine response after stimulation of keratinocytes with Propionibacterium acnes and coproporphyrin III.

BACKGROUND: The inflammation in acne vulgaris is widely thought to be induced by an immunological reaction, but the role of Propionibacterium acnes is unclear. OBJECTIVES: To examine the local host response mechanism of a keratinocyte cell line 3 h and 6 h after stimulation with viable and heat-killed P. acnes. METHODS: The quantitative expression of cytokines was measured at the mRNA level by real-time reverse transcription-polymerase chain reaction. RESULTS: The coincubation of a keratinocyte cell line with viable, but not heat-killed, P. acnes modulated an adequate cytokine response for interleukin (IL)-1beta, granulocyte/macrophage colony-stimulating factor and IL-8. High-performance liquid chromatographic analysis of the in vivo porphyrin pattern secreted by P. acnes revealed a predominance of coproporphyrin III in acne lesions. This same porphyrin fraction also modestly induced IL-8 expression by keratinocytes. CONCLUSIONS: This cytokine pattern may favour a chemotactic response and implicates P. acnes and coproporphyrin III in the recruitment of inflammatory cells to the site of infection and in the development of acne lesions.

Acne Vulgaris↗
PubMed2005

RU 58841-myristate--prodrug development for topical treatment of acne and androgenetic alopecia.

Acne and androgenetic alopecia are linked to androgen effects and therefore should improve following topical application of antiandrogens. We present a new antiandrogen prodrug, RU 58841-myristate (RUM) for topical therapy. Almost devoid of affinity to the androgen receptor, as derived from investigations in the mouse fibroblast cell line 29 +/GR +, RUM is rapidly metabolised to the potent antiandrogen RU 58841 by cultured human foreskin fibroblasts and keratinocytes, male occipital scalp skin dermal papilla cells, and by cells of the sebaceous gland cell line SZ95. In order to improve a specific targeting of the hair follicle, RUM was loaded on solid lipid nanoparticles (SLN), which are already known to support dermal targeting effects. Physically stable RUM loaded SLN were produced by hot homogenization. Penetration/permeation studies carried out using the Franz diffusion cell proved only negligible permeation of reconstructed epidermis and excised porcine skin within 6 h, implying a more topical action of the drug. Targeting to the hair follicle using SLN was visualised by fluorescence microscopy, following the application of Nile Red labelled SLN to human scalp skin. Transmission electron microscopy (TEM) allowed to detect intact silver labelled SLN in porcine hair follicles of preparations applied to the skin for 24 h. RUM loaded SLN should be considered for topical antiandrogen therapy of acne and androgenetic alopecia.

Acne Vulgaris↗
PubMed2004

Raised levels of anti-glucose-6-phosphate isomerase IgG in serum and synovial fluid from patients with inflammatory arthritis.

BACKGROUND: In K/BxN mice, anti-glucose-6-phosphate isomerase (GPI) antibodies (Abs) are arthritogenic, and their transfer into naive mice induces arthritis. Anti-GPI Abs develop in many human patients with RA and are associated with more severe forms of the disease. OBJECTIVE: To elucidate the serum and synovial fluid (SF) anti-GPI IgG profiles among different patient groups with a variety of arthritides. METHODS: Blood and SF obtained concomitantly from 91 patients with clinically well defined arthritis were tested for concentrations of total anti-GPI IgG, anti-GPI IgG subclasses, B lymphocyte stimulator (BLyS), and APRIL by ELISA. RESULTS: Anti-GPI IgG was detected in sera and SF of patients with many arthritic diseases, but was preferentially associated with inflammatory arthritis, in general, and RA, in particular. The anti-GPI IgG subclass usage was skewed and varied among the different arthritic disease groups. Inverse correlations between serum levels of BLyS and anti-GPI IgG and positive correlations between serum levels of APRIL and anti-GPI IgG were seen among immune based arthritic patients and patients with RA but not among non-immune based patients. No correlations were found in SF from any group of arthritic patients. CONCLUSION: Raised circulating anti-GPI Abs are not unique to patients with RA but are present in many patients with inflammatory arthritis. The difference in anti-GPI IgG subclass usage among disease groups may influence effector function and disease outcome. The inverse correlation between serum BLyS and anti-GPI IgG levels suggests that anti-GPI B cells may be regulated differently from other autoantibody producing B cells. Anti-GPI Abs may serve a pathogenic function in humans by promoting the maintenance of existing disease.

Adult↗
PubMed2002

Design and application of a new modular adapter for laser diffraction characterization of inhalation aerosols.

An inhaler adapter has been designed for the characterization of the aerosol clouds from medical aerosol generators such as nebulizers, dry powder inhalers (dpis) and metered dose inhalers (mdis) with laser diffraction technology. The adapter has a pre-separator, for separation of large particles (i.e. carrier crystals) from the aerosol cloud before it is exposed to the laser beam. It also has a fine particle collector for measuring the emitted mass fraction of fines by chemical detection methods after laser diffraction sizing. The closed system enables flow control through the aerosol generators and all test conditions, including ambient temperature and relative humidity, are automatically recorded. Counter flows minimize particle deposition onto the two windows for the laser beam, which make successive measurements without cleaning of these windows possible. The adapter has successfully been tested for nebulizers, mdis and dpis. In a comparative study with ten nebulizers it was found that these devices differ considerably in droplet size (distribution) of the aerosol cloud for the same 10% aqueous tobramycin solution (volume median diameters ranging from 1.25 to 3.25 microm) when they are used under the conditions recommended by the manufacturers. The droplet size distribution generated by the Sidestream (with PortaNeb compressor) is very constant during nebulization until dry running of the device. Comparative testing of dpis containing spherical pellet type of formulations for the drug (e.g. the AstraZeneca Turbuhaler) with the adapter is fast and simple. But also formulations containing larger carrier material could successfully be measured. Disintegration efficiency of a test inhaler with carrier retainment (acting as a pre-separator) could be measured quite accurately both for a colistin sulfate formulation with 16.7% of a lactose fraction 106-150 microm and for a budesonide formulation with a carrier mixture of Pharmatose 325 and 150 M. Therefore, it is concluded that, with this special adapter, laser diffraction may be a valuable tool for comparative inhaler evaluation, device development, powder formulation and quality control. Compared to cascade impactor analysis, laser diffraction is much faster. In addition to that, more detailed and also different information about the aerosol cloud is obtained.

Administration, Inhalation↗
PubMed2002

Invasion of human keratinocytes by Staphylococcus aureus and intracellular bacterial persistence represent haemolysin-independent virulence mechanisms that are followed by features of necrotic and apoptotic keratinocyte cell death.

BACKGROUND: Colonization of human skin by Staphylococcus aureus is a characteristic feature of several inflammatory skin diseases, which is often followed by tissue invasion and severe cell damage. A crucial role has been attributed to staphylococcal haemolysins in the cytotoxicity to epidermal structures. OBJECTIVES: To investigate haemolysin-independent virulence to human keratinocytes. METHODS: The stable alpha-haemolysin, beta-haemolysin double-negative S. aureus mutant DU 5720 was compared with the fully virulent parent strain 8325-4 and with its isogenic fibronectin-binding protein A/B-negative variant DU 5883 in an invasion model. RESULTS: This assay showed dose-dependent internalization of all the strains investigated by human HaCaT keratinocytes, with reduced internalization of DU 5883. Transmission electron microscopy revealed adhesion of staphylococci to cellular pilus-like extrusions, followed by the embedding of the bacteria in cellular grooves. Following attachment to the keratinocytes the staphylococci were engulfed into vesicles within the cytoplasm where some bacteria persisted for 24-48 h. Addition of cytochalasin D strongly reduced the bacterial uptake, suggesting an active keratinocyte process. Bacterial invasion was followed by severe keratinocyte cell damage showing the morphological changes of cytotoxic and, to a lesser extent, apoptotic cell death as determined by the trypan blue exclusion test and the terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labelling assay. The highest levels of lethal cytotoxicity were observed in haemolysin-producing strains, whereas the induction of apoptosis seemed to depend on internalization. CONCLUSIONS: Staphylococcal invasion of human keratinocytes represents a potent staphylococcal virulence factor, which, independently of alpha- and beta-haemolysins, leads to necrotic and apoptotic cell damage.

Apoptosis↗
PubMed2002

Drug targeting by solid lipid nanoparticles for dermal use.

Long term topical glucocorticoid treatment can induce skin atrophy by the inhibition of fibroblasts. We, therefore, looked for the newly developed drug carriers that may contribute to a reduction of this risk by an epidermal targeting. Prednicarbate (PC, 0.25%) was incorporated into solid lipid nanoparticles of various compositions. Conventional PC cream of 0.25% and ointment served for reference. Local tolerability as well as drug penetration and metabolism were studied in excised human skin and reconstructed epidermis. With the latter drug recovery from the acceptor medium was about 2% of the applied amount following PC cream and ointment but 6.65% following nanoparticle dispersion. Most interestingly, PC incorporation into nanoparticles appeared to induce a localizing effect in the epidermal layer which was pronounced at 6 h and declined later. Dilution of the PC-loaded nanoparticle preparation with cream (1:9) did not reduce the targeting effect while adding drug-free nanoparticles to PC cream did not induce PC targeting. Therefore, the targeting effect is closely related to the PC-nanoparticles and not a result of either the specific lipid or PC adsorbance to the surface of the formerly drug free nanoparticles. Lipid nanoparticle-induced epidermal targeting may increase the benefit/risk ratio of topical therapy.

Administration, Cutaneous↗
PubMed2002

[Mode of action of ciclopiroxolamine on Candida albicans].

Candida albicans is a common pathogen causing both superficial and invasive mycoses. The hydroxypyridone ciclopiroxolamine belongs to antimycotic drugs used for treatment of superficial mycoses. Whereas the mode of action of other antimycotics, for example the azoles, is well known, the specific action of ciclopiroxolamine is poorly understood. There are hints, that ciclopiroxolamine acts as a potential chelating agent and influences some cellular processes by chelating metal ions. Consequently, the antimycotic effectiveness of ciclopiroxolamine could be due to a general reduced viability of the fungus, or due to a higher sensitivity of a fungus against the human immune system as well as due to a reduced capability to produce some specific virulence factors that are indispensable for infection. Nevertheless, iron metabolism seems to play a major role in its effect.

Candida albicans↗
PubMed2002

The secreted aspartic proteinases as a new target in the therapy of candidiasis.

Secreted aspartic proteinases (Saps) are important virulence factors in different types of candidiasis caused by Candida albicans (C. albicans). The various isoenzymes are expected to fulfil different tasks during mucosal or disseminated infections. It could be shown that the introduction of the proteinase inhibitors like saquinavir and indinavir in the therapy of human immunodeficiency virus (HIV) infected patients has an effect on Sap activity in vitro as well as in vivo. Therefore, drugs like the HIV proteinase inhibitors could play an essential role in the treatment of candidiasis in the future, especially if further adapted to this target.

Aspartic Acid Endopeptidases↗
PubMed2001

[New developments in medical mycology].

Not only have the systemic mycoses clearly increased in number but also mycoses of the skin are more common than presumed in the past. Today onychomycosis is found in up to 10% of human beings. Onychomycosis can compromise quality of life markedly. Common tinea pedis is one of the most important risk factors for erysipelas of the lower legs. The clinical presentation of oral candidosis in HIV-infected patients is changing; Candida dubliniensis has been identified as another important causative microorganism. Onychomycosis today in most cases can be cured using terbinafine or itraconazole. When choosing the ideal drug in a given case, both the benefit risk ratio and the benefit cost ratio have to be taken into account. Liposomally encapsulated amphotericin B represents a major breakthrough in the treatment of systemic mycoses or fever of unknown origin. The same applies to liposomally encapsulated econazole with respect to tinea pedis. In regard to the pathogenesis of Candida infections the family of secreted aspartic proteinases plays a major role as a virulence factor and possible future target for antimycotic treatment.

AIDS-Related Opportunistic Infections↗
PubMed2001

Current and future approaches to antimycotic treatment in the era of resistant fungi and immunocompromised hosts.

Due to the ever-increasing number of immunocompromised patients, both localised and life-threatening systemic fungal infections are on the increase. Conventional treatment is of limited help, not in the least due to a less optimum benefit-to-risk ratio. Moreover, emerging pathogens with reduced antimicrobial susceptibility and the development of resistance in Candida albicans form a new challenge. Fortunately, conventional antimycotics have been improved and entirely new ones are on the horizon as well as alternative approaches such as immunoreconstitution.

Antifungal Agents↗
PubMed2001

Mononuclear cells ingest E. coli opsonized by investigational intravenous immunoglobulin preparations in the absence of complement more efficiently than polymorphonuclear phagocytes.

OBJECTIVE: The increasing use of intravenous immunoglobulins (IVIg) to treat systemic inflammatory, mostly autoimmune, diseases raises the concern that their competition for FcgammaReceptor (FcgammaR) binding with immune complexes might interfere with the removal of opsonized microbial agents more than it favoured their opsonophagocytosis. METHODS: Using a sensitive FACS-based phagocytosis assay allowing for the identification of the phagocytosing cell-type, we have tested the relative capacity of Pentaglobin and two investigational IVIg preparations, IVIgG and IVIgM, to promote E. coli phagocytosis. The plasma IL-8 levels 4 h after phagocytosis were measured by ELISA. RESULTS: Heat inactivated, complement (C) depleted serum allowed about 25% polymorphonuclear leukocytes (PMNLs) and 15% monocytes (MNs) of 16 donors to phagocyte E. coli. The addition of IVIg favoured mean phagocytosis by MNs to 55%, but by PMNLs only to 25%. The addition of fresh autologous plasma as a C source resulted in a boost of phagocytosing capacity to reach >90% of the PMNLs and >72% of the MNs. Blockade of FcgammaRII and FcgammaRI using monoclonal antibodies (mAb) reduced phagocytosis and IL-8 release. CONCLUSION: We conclude that excess IVIgG/M preparations added to a phagocytic system of PMNLs and MNs, without preopsonization of E. coli, promotes phagocytosis as expected, but MNs rather than PMNLs do this more thoroughly on their own.

Escherichia coli↗
PubMed2001

Autoantibodies to GPI in rheumatoid arthritis: linkage between an animal model and human disease.

In K/BxN T cell receptor-transgenic mice, spontaneous inflammatory arthritis exhibiting many of the features of human rheumatoid arthritis (RA) is initiated by T cells, but is almost entirely sustained by antibodies to the self-antigen glucose-6-phosphate isomerase (GPI). The relevance of these observations to human disease has been questioned. Here we show that 64% of humans with RA, but not controls, had increased concentrations of anti-GPI immunoglobulin G (IgG) in serum and synovial fluid. In addition, the concentrations of soluble GPI in the sera and synovial fluids of RA patients were also elevated, which led to immune complex formation. Using phage-display methods, we cloned a panel of specific high-affinity human monoclonal anti-GPI IgGs from a patient with RA. These antibodies were highly somatically mutated, which was indicative of an affinity-matured response that was antigen driven. Immunohistochemistry of RA synovium showed high concentrations of GPI on the surface of the synovial lining and on the endothelial cell surface of arterioles; this indicated a mechanism by which antibodies to GPI may precipitate joint disease. The results indicate that the immunological events that lead to the development of autoimmune disease in the K/BxN mouse model may also occur in human RA. This data may be used to develop new strategies for therapeutic intervention.

Amino Acid Sequence↗
PubMed2001

The KEX2 gene of Candida glabrata is required for cell surface integrity.

Candida glabrata has emerged as one of the most common causes of candidosis. In order to identify factors that are necessary for viability and pathogenicity of this fungal pathogen, we analysed the role of the KEX2 gene, which codes for a regulatory endoproteinase that is known to process certain virulence factors in Candida albicans. The KEX2 gene from C. glabrata was cloned and found to have 51% and 62% identity and high structural similarities to the homologous counterparts in C. albicans and Saccharomyces cerevisiae. KEX2 was expressed at all time points investigated during growth in complex medium. In order to investigate the role of this putative regulatory proteinase, Kex2-deficient mutants were produced. In addition to known kex2 phenotypes, such as pH and calcium hypersensitivity, the mutants grew in cellular aggregates and were found to be hypersensitive to several antifungal drugs that target the cell membrane, including azoles, amorolfine and amphotericin B. Ultrastructural investigation after exposure to low doses of itraconazole showed azole-specific alterations such as enlarged vacuoles and proliferation of the cytoplasmatic membrane in the kex2 mutants, but not in the control strains. In contrast, antifungals such as 5-flucytosine and hydroxypyridones inhibited growth of the kex2 mutants and the control strains to the same extent. In an in vitro model of oral candidosis, kex2 mutants showed reduced tissue damage in the presence of itraconazole compared with the control infections. These data suggest that Kex2 is involved in the processing of proteins that are essential for cell surface integrity of C. glabrata.

Amino Acid Sequence↗
PubMed2001

Evidence of a leading role for VEGF in Bartonella henselae-induced endothelial cell proliferations.

Bartonella henselae causes the vasculoproliferative disorders bacillary angiomatosis (BA) and bacillary peliosis (BP). The pathomechanisms of these tumorous proliferations are unknown. Our results suggest a novel bacterial two-step pathogenicity strategy, in which the pathogen triggers growth factor production for subsequent proliferation of its own host cells. In fact, B. henselae induces host cell production of the angiogenic factor vascular endothelial growth factor (VEGF), leading to proliferation of endothelial cells. The presence of B. henselae pili was associated with host cell VEGF production, as a Pil- mutant of B. henselae was unable to induce VEGF production. In turn, VEGF-stimulated endothelial cells promoted the growth of B. henselae. Immunohistochemistry for VEGF in specimens from patients with BA or BP revealed increased VEGF expression in vivo. These findings suggest a novel bacteria-dependent mechanism of tumour growth.

Angiomatosis, Bacillary↗