[Primary cutaneous cryptococcosis : Pigeons can carry more than letters !] / Primär kutane Kryptokokkose : Tauben können mehr als Briefe transportieren !

In the event of non-specific epidermal lesions, the importance of a comprehensive anamnesis becomes especially apparent. In the following, we report on a patient case in which only a focused anamnesis was able to bring light into the darkness of numerous differential diagnoses - and to produce the diagnosis of a rare but in this collective common illness: primary cutaneous cryptococcosis.

Strategies for the identification and analysis of viral immune-evasive genes--cytomegalovirus as an example.

Co-evolution of herpesviruses with their hosts has resulted in multiple interactions between viral genes and cellular functions. Some interactions control genomic maintenance and replication in specific tissues, other affect the immune control at various stages. Few immunomodulatory functions of genes can be predicted by sequence homology. The majority of genes with immunomodulatory properties only become apparent in functional assays. This chapter reviews procedures which have been used for successful identification of immunomodulatory genes in the past and deals with recent methods which may be applicable for the identification of additional immunomodulatory functions unknown so far.

Macrophages escape inhibition of major histocompatibility complex class I-dependent antigen presentation by cytomegalovirus.

The mouse cytomegalovirus (MCMV) m152- and m06-encoded glycoproteins gp40 and gp48, respectively, independently downregulate major histocompatibility complex (MHC) class I surface expression during the course of productive MCMV infection in fibroblasts. As a result, presentation of an immediate-early protein pp89-derived nonapeptide to H-2L(d)-restricted CD8(+) cytotoxic T cells is completely prevented in fibroblasts. Here we demonstrate that MCMV-infected primary bone marrow macrophages and the macrophage cell line J774 constitutively present pp89 peptides during permissive MCMV infection to cytotoxic T lymphocytes (CTL). In contrast to fibroblasts, expression of the m152 and m06 genes in macrophages does not affect surface expression of MHC class I. Assessment of pp89 synthesis and quantification of extracted peptide revealed a significantly higher efficiency of macrophages than of fibroblasts to process pp89 into finally trimmed peptide. The yield of pp89 peptide determined in MCMV-infected tissues of bone marrow chimeras confirmed that bone marrow-derived cells represent a prime source of pp89 processing in parenchymal organs. The finding that macrophages resist the viral control of MHC I-dependent antigen presentation reconciles the paradox of efficient induction of CMV-specific CD8(+) CTL in vivo despite extensive potential of CMVs to subvert MHC class I.

Cytomegaloviral control of MHC class I function in the mouse.

Cytomegaloviruses (CMVs) represent prototypic viruses of the beta-subgroup of herpesviruses. Murine cytomegalovirus (MCMV) infects mice as its natural host. Among viruses, CMVs have evolved the most extensive genetic repertoire to subvert MHC class I functions. To date three MCMV proteins have been identified which affect MHC I complexes. They are encoded by members of large virus-specific gene families located at either flanking region of the 235 kb MCMV genome. The MHC I subversive genes belong to the early class of genes and code for type I transmembrane glycoproteins. The m152-encoded 37/40 kDa glycoprotein interacts with MHC I transiently and retains class I complexes in the endoplasmic reticulum (ER) Golgi intermediate compartment on its journey to the endolysosome. In contrast, the m06-encoded glycoprotein of 48 kDa complexes tightly with ternary MHC class I molecules in the FR. Due to sorting signals in its cytoplasmic tail, gp48 redirects MHC I to endolysosomal compartments for proteolytic destruction. Likewise, the 34 kDa glycoprotein encoded by m04 binds tightly to MHC class I complexes in the ER but the gp34/MHC I complex reaches the plasma membrane. The CD8+ T-cell-dependent attenuation of a m152 deletion mutant virus proves for the first time that inhibition of antigen presentation is indeed essential for the biological fitness of CMVs in vivo.

[Algorithm of endometrial meta- and hyperplasia]. / Algorithmus der endometrialen Meta- und Hyperplasien.

As to to their frequency and variety, endometrial meta- and hyperplasias are the most impressive examples of the growth and differentiation potential of the Muellerian system and the inductive power of steroid hormones and related inter- and intracellular factors. Characteristic steroid reactions are the glandular hyperplasias, ciliated and squamous cell metaplasias in the case of hyperestrogenism, and the mucinous and clear cell meta- and hyperplasias in the case of gestagen excess. In 1994, the WHO established a new classification of endometrial hyperplasias. This classification takes into account the profound differences in cancer risk, and accordingly demands a clearcut distinction between simple and complex (steroid sensitive, almost always reversible) hyperplasias without atypia, and simple and complex (partial steroid resistant and potential progressive) hyperplasias with atypia. The conclusion drawn from clinical experience is, that the atypical endometrial hyperplasia--and this alone--is the precancerous lesion of the ordinary endometroid carcinoma. In contrast, it is still not clear which biological significance accounts to all the complex squamous, mucinous, clear cell and ciliated cell meta- and hyperplasias. Yet, it is good pathological and clinical practice, to upgrade any metaplastic lesion with nuclear atypia, and to remove the uterus as it is done in almost all atypical endometrial hyperplasias.

[Algorithm of clinical aspects and pathology of endometrial carcinoma]. / Algorithmus der Klinik und Pathologie des Endometriumkarzinoms.

The carcinoma of the endometrium is the most common malignancy seen in the female pelvic genital organs. Important risk factors are age and unopposed estrogen (both endogenous and exogenous). In comparison, the association of antiestrogens (e.g., tamoxifen) and endometrial cancer is rather small, as yet. Fortunately, survival is high because the majority of patients have in common the presence of a low grade, low stage carcinoma of the endometroid type which gives rise to vaginal bleeding and forces the patients to attend the gynecologist. Special screening studies (e.g. vaginal sonography) to evaluate the endometrium are not indicated in the asymptomatic patient without risk factors. Tumor type, grading, and--most importantly--the depth of myoinvasion and the extent of extrauterine disease are the prognostic indicators that allow differential treatment, and help to identify patients at high risk vs. low risk for recurrent disease. Investigations of growth fraction, ploidy, steroid receptors, K-ras or p53 may be a supplement for dissecting special subgroups, but do not influence the clinical regimen, as yet. Most patients with stage I cancer are cured by surgery alone. Patients successfully treated for endometrial cancer should enjoy the benefits of estrogen replacement therapy, since they do not bear a risk of increased recurrence of their disease. Radiation therapy will be given to patients with incomplete resection of pelvic disease and/or extensive lymphonodal involvement, especially paraaortal lymph node metastasis. As yet, there is no rationale for an adjuvant hormone-(gestagen-) or chemotherapy. An exception, however, is the (mostly palliative) treatment of recurrent disease.

A cytomegalovirus glycoprotein re-routes MHC class I complexes to lysosomes for degradation.

Mouse cytomegalovirus (MCMV) early gene expression interferes with the major histocompatibility complex class I (MHC class I) pathway of antigen presentation. Here we identify a 48 kDa type I transmembrane glycoprotein encoded by the MCMV early gene m06, which tightly binds to properly folded beta2-microglobulin (beta2m)-associated MHC class I molecules in the endoplasmic reticulum (ER). This association is mediated by the lumenal/transmembrane part of the protein. gp48-MHC class I complexes are transported out of the ER, pass the Golgi, but instead of being expressed on the cell surface, they are redirected to the endocytic route and rapidly degraded in a Lamp-1(+) compartment. As a result, m06-expressing cells are impaired in presenting antigenic peptides to CD8(+) T cells. The cytoplasmic tail of gp48 contains two di-leucine motifs. Mutation of the membrane-proximal di-leucine motif of gp48 restored surface expression of MHC class I, while mutation of the distal one had no effect. The results establish a novel viral mechanism for downregulation of MHC class I molecules by directly binding surface-destined MHC complexes and exploiting the cellular di-leucine sorting machinery for lysosomal degradation.

Cytokine regulation of the balance between alloindifferent and allospecific suppressor induction in mixed lymphocyte cultures.

The effects of exogenous cytokines on the generation of alloindifferent, MHC-unrestricted suppressive activity early on in mixed lymphocyte culture interactions have been investigated. Interleukin 4 strongly blocked the generation of suppression, whereas IL-1, IL-2, and IL-6 enhanced it to some extent. Tumor necrosis factor-alpha, interferons-alpha and -gamma, granulocyte/macrophage colony-stimulating factor, granulocyte CSF, IL-3 and IL-5, and a number of combinations of these factors were without effect in this system. Insofar as the alloindifferent suppression studied here also inhibited the development of allospecific, MHC restricted suppressive activity later in MLC, reduction by IL-4 of its development may have relevance for the use of this cytokine to facilitate the induction of specific suppressor cell-mediated transplantation tolerance in vivo.

Regulation of allospecific suppressive cell generation in vitro.

Control of the generation of suppressive cells (SC) in allogeneic mixed lymphocyte cultures (MLC) has been re-investigated. Cells taken from 3-6 days old ("early", e-MLC) suppressed lymphocyte proliferative responses when transferred to a second MLC. Suppression was not allospecific, nor restricted to the autologous responder. In contrast, cells from MLC 7-10 days old ("late", l-MLC) mediated weak but specific suppressive activity, which was HLA-restricted. Addition of early MLC cells (e-MLC1) to a second MLC (MLC2), blocked the further generation of non-specific suppressive activity in that MLC, suggesting the presence of downregulatory components for SC generation. Nonetheless, the generation of allospecific suppression in late MLC2 (l-MLC2) was enhanced rather than inhibited under these conditions. In separate experiments, a T cell clone (TCC) was isolated which mimicked the action of e-MLC cells on SC generation, namely, down-regulation of non-specific but amplification of specific SC generation. This clone carried the "alternative" tau/delta T cell receptor. Thus, tau/delta+ "antisuppressor" regulatory cells may have a role in the establishment and maintenance of allograft tolerance.

[Anti-ischemic effects of SIN-1, a molsidomine metabolite, during coronary angioplasty and antiplatelet effects in humans]. / Effets anti-ischémiques du SIN-1, métabolite de la molsidomine, au cours de l'angioplastie coronarienne et effets antiplaquettaires chez l'homme.

The effects of SIN-1, the biologically active metabolite of molsidomine, on tolerance of ischaemia during percutaneous transluminal coronary angioplasty were studied in 12 patients. Following an intracoronary injection of SIN-1 0.5 mg, the time required for the ST segment to be depressed by at least 0.2 mV was significantly prolonged from 44 to 55-62 seconds. Simultaneously, SIN-1 reduced the significant rise in left ventricular end-diastolic pressure observed during dilatation. One minute after SIN-1 was injected, no effect was noted or on the increase in left ventricular volume indices or on the reduction of ejection fraction associated with dilatation. The maximum anti-ischaemic effect of SIN-1 was obtained 5 minutes after the injection. As regards the mechanism of action of the drug, a decrease in parietal tension through reduction of left ventricular preload should be considered. In addition, strong inhibition of platelet aggregation and adenosine triphosphate secretion was demonstrated in high platelet content plasma and whole blood 2 hours after an oral 16 mg dose of molsidomine. The antiplatelet effect of molsidomine may contribute to its anti-ischaemic effect by reducing both platelet adherence at the site of dilatation and the release of vasoconstrictor and pro-aggregant mediators.