Gustatory and olfactory function in patients with granulomatosis with polyangiitis (Wegener's).

OBJECTIVES: Recent findings suggest that autoimmune disorders predispose to a diminished capacity to taste and smell. This has been shown for patients with systemic lupus erythematosus as well as for patients with rheumatoid arthritis (RA). Granulomatosis with polyangiitis (GPA), with its particular manifestations in the upper respiratory tract, may therefore have an even higher impact on these senses. The aims of this study were to evaluate the gustatory and olfactory function in patients with GPA, to compare them to sex- and age-matched healthy controls, and to correlate these findings with their GPA disease severity. METHOD: Patients with established GPA were analysed by standardized assessments for gustatory and olfactory functions and examined for disease activity, stage of disease, and treatment. RESULTS: Forty-four GPA patients were tested for their chemosensory functions. Compared to age- and sex-matched healthy controls, GPA patients showed significantly decreased olfactory scores along with diminished scores for their gustatory functions. The diminished sense of smell in GPA patients correlated significantly with elevated C-reactive protein (CRP) values whereas the gustatory impairment correlated with the duration and extent of the disease. CONCLUSIONS: Our results indicate that olfactory and gustatory functions are significantly decreased in GPA. As the olfactory function of these patients was comparable to patients with RA, chemosensory impairment may not simply be a consequence of the involvement of the upper respiratory tract, but rather a common complication of systemic autoimmune diseases.

[Sarcoidosis of lymph nodes in the submandibular compartment]. / Lymphknotensarkoidose der Submandibularisloge.

Sarcoidosis is a granulomatous systemic disease of unknown etiology. Besides the landmark pulmonary lesions, extrathoracic manifestations of the disease can also occur. We report the case of a 53-year-old woman with an obscure swelling of both submandibular compartments. The radiological and pathohistological evaluations confirmed the uncommon diagnosis of sarcoidosis of the submandibular compartment. The tumor in each compartment consisted of a huge lymph node conglomerate respectively displacing the submandibular gland. The major salivary glands and the thorax were not involved.

Expression of DARC, CXCR3 and CCR5 in giant cell arteritis.

OBJECTIVES: Leucocyte infiltration is the hallmark of vasculitis, chemokines being mainly responsible for leucocyte migration into inflamed tissues. The objective was to evaluate the local expression of chemokines and chemokine receptors in biopsies of patients with giant cell arteritis (GCA) compared with arteries from patients with polymyalgia rheumatica (PMR). We studied the expression of CCR5, CXCR3 and that of the Duffy antigen/receptor of chemokine (DARC), a chemokine internalizing receptor (interceptor), in parallel to the expression of the CCR5 ligand RANTES/CCL5. METHODS: Paraffin-embedded tissue sections from six patients with GCA and five patients with PMR were available for immunohistological analysis of chemokine receptor expression. RANTES/CCL5 mRNA was detected in tissue sections by in situ hybridization. RESULTS: In patients with biopsy-proven giant cell arteritis, CCR5 and CXCR3 were highly expressed by infiltrating leucocytes in involved tissue sections. Predominant clustering of CCR5+ and CXCR3+ leucocytes was found in the adventitia and was co-localized with the expression of CCL5/RANTES mRNA. Interestingly, we found marked expression of DARC on adventitial high endothelial venules in vasculitis lesions of patients with GCA, while in arteries from patients with PMR DARC was only expressed on a low number of vessels with flat lining endothelium. CONCLUSIONS: The co-localization of infiltrating CCR5+ and CXCR3+ leucocytes together with CCL5/RANTES and DARC in vasculitis lesions suggests a role for these chemokine receptors in leucocyte infiltration, possibly supported by DARC-mediated vascular presentation of chemokines.

Cell type-specific induction of O6-alkylguanine-DNA alkyltransferase mRNA expression in rat liver during regeneration, inflammation and preneoplasia.

PURPOSE AND METHODS: To investigate the potential role of an aberrant cellular DNA repair in target cells during malignant transformation we studied cell type-specific mRNA expression of the DNA repair protein O6-alkylguanine-DNA alkyltransferase (O6-AGT) in normal and regenerating rat liver, chronic hepatitis and preneoplastic liver lesions by in situ hybridization and semiautomatic image analysis. RESULTS: O6-AGT mRNA expression was found to be four to five times higher in hepatocytes than in nonparenchymal cells. A 1.9-fold increase in O6-AGT mRNA was observed after partial hepatectomy. Intraperitoneal injection of diethylnitrosamine led to a 1.3-fold and 2.6-fold rise in periportal and perivenous hepatocytes, respectively. Ethylnitrosourea produced an enhancement of mRNA levels up to 1.6-fold in hepatocytes without regional differences. In megalocytic hepatocytes of Long-Evans Cinnamon rats with chronic hepatitis, a 4.4-fold mRNA induction was found. In small preneoplastic lesions induced after chronic diethylnitrosamine-exposure, O6-AGT mRNA expression was identical to that of adjacent normal tissue. Intermediate and large lesions revealed 1.5- to 1.6-fold higher mRNA levels. CONCLUSIONS: These results suggest an induction of O6-AGT mRNA expression in hepatocellular target tissue under conditions of increased carcinogen sensitivity . The O6-AGT expression in early preneoplastic lesions did not differ from normal surrounding liver tissue, thus excluding the possibility that progression of preneoplasia in rat liver is associated with a deficient mRNA expression of this DNA repair protein. On the contrary, enhanced O6-AGT mRNA expression in more advanced foci and early neoplastic nodules may confer a selective advantage upon early malignant hepatocytes with regard to further tumor progression.

Stavudine versus zidovudine and the development of lipodystrophy.

The pathogenesis of some components of the lipodystrophy (LD) syndrome might be linked to the use of nucleosides. Earlier reports did not compare treatment regimens according to the nucleoside backbone. We studied a cohort of individuals who did not switch between stavudine and zidovudine. LD was defined to be present if one of three criteria was met: self-report by the patient, observation by an investigator who had known the patient since commencement of highly active antiretroviral therapy (HAART), or examination by a physician masked to therapy. The mean duration of therapy was 101 weeks (range: 26-234 weeks). Overall prevalence of LD was 48.7%. Lipoatrophy and lipohypertrophy occurred in 33.9% and 28.7% of patients, respectively. Logistic regression showed four parameters to be significantly associated with lipoatrophy: HAART longer than 2 years (p =.002, odds ratio [OR] = 4.4, 95% confidence interval [CI]: 1.608-11.965), baseline viral load >100,000 copies/ml (p =.004, OR = 4.3, CI: 1.726-11.197), age >40 years (p =.016, OR = 3.2, CI: 1.247-8.373), and white ethnicity (p =.041, OR = 5.4, CI: 1.070-28.184). Cholesterol levels of >200 mg/dl at baseline were associated with a risk reduction (p =.047, OR = 0.36, CI: 0.130-0.987). Use of lipohypertrophy as a dependent variable resulted in a significant association with HAART duration (p = 0.028, OR = 2.7, CI: 1.2-6.5) and protease inhibitor use (p =.014, OR = 3.8, CI: 1.3-11.2). LD prevalence is similar with both backbones using stavudine or zidovudine. This is the first time that baseline cholesterol was shown to be significantly associated with lipoatrophy.

Expression and characterization of the chemokine receptors CCR2 and CCR5 in mice.

The chemokine receptors CCR2 and CCR5 play important roles in the recruitment of monocytes/macrophages and T cells. To better understand the role of both receptors in murine models of inflammatory diseases and to recognize potential problems when correlating these data to humans, we have generated mAbs against murine CCR2 and CCR5. In mice CCR2 is homogeneously expressed on monocytes and on 2--15% of T cells, closely resembling the expression pattern in humans. In contrast to humans, murine NK cells are highly CCR5 positive. In addition, CCR5 is expressed on 3--10% of CD4 and 10--40% of CD8-positive T cells and is weakly detectable on monocytes. Using a model of immune complex nephritis, we examined the effects of inflammation on chemokine receptor expression and found a 10-fold enrichment of CCR5(+) and CCR2(+) T cells in the inflamed kidneys. The activity of various chemokines and the antagonistic properties of the mAbs were measured by ligand-induced internalization of CCR2 and CCR5 on primary leukocytes. The Ab MC-21 (anti-CCR2) reduced the activity of murine monocyte chemotactic protein 1 by 95%, whereas the Ab MC-68 (anti-CCR5) blocked over 99% of the macrophage-inflammatory protein 1alpha and RANTES activity. MC-21 and MC-68 efficiently blocked the ligand binding to CCR2 and CCR5 with an IC(50) of 0.09 and 0.6--1.0 microg/ml, respectively. In good correlation to these in vitro data, MC-21 almost completely prevented the influx of monocytes in thioglycollate-induced peritonitis. Therefore, both Abs appear as useful reagents to further study the role of CCR2 and CCR5 in murine disease models.

The apoptosis mediator mDAP-3 is a novel member of a conserved family of mitochondrial proteins.

Programmed cell death is essential for organ development and regeneration. To identify molecules relevant for this process, full length cDNA cloning of a short, developmentally regulated murine cDNA fragment, MERM-3, was performed and showed a 1.7 kb mRNA encoding a 45 kDa protein with an ATP/GTP binding motive (P-loop). Sequence analysis revealed an 82% amino acid identity to the human death associated protein 3 (hDAP-3), a positive mediator of apoptosis. The full length sequence being the murine orthologue of hDAP-3 is therefore referred to as mDAP-3. In situ hybridization and northern blot analysis showed an abundant mRNA expression with a pronounced expression in highly proliferative epithelial compartments. For mDAP-3, cytochrome c release and induction of cell death could be demonstrated by overexpression of a mDAP-3/EGFP fusion protein. DAP-3 mediated apoptosis was shown to depend on a functional P-loop. Intracellular localization studies using the mDAP-3/EGFP fusion protein, cell fractionation and protease protection experiments localized mDAP-3 to the mitochondrial matrix. DAP-3, in contrast to cytochrome c, retained its mitochondrial localization during apoptosis induction. A mutant of a putative yeast orthologue of mDAP-3, YGL129c, here referred to as yDAP-3, has been shown to exhibit disrupted mitochondrial function. yDAP-3 deficient mutants could be shown to progressively loose mitochondrial DNA. Loss of mitochondrial DNA in yDAP-3 was partially prevented by transfection of the yDAP-3 deficient mutant with mDAP-3, indicating functional complementation by murine DAP-3 in the yeast system. These data identify mDAP-3 as one of the first proapoptotic factors in the mitochondrial matrix and provide evidence for a critical, evolutionary conserved role of members of the DAP-3 protein family for mitochondrial biogenesis.

The sign of Leser-Trélat: a paraneoplastic cutaneous syndrome that facilitates early diagnosis of occult cancer.

The sign of Leser-Trélat has been described as a rare cutaneous marker of internal malignancy. We report a patient presenting with the sign of Leser-Trélat, in whom a limited diagnostic workup for an associated malignancy lead to the early diagnosis of asymptomatic renal cell carcinoma and curative tumor nephrectomy. A review on this and other cutaneous paraneoplastic syndromes is given. Since they may be the only presenting sign of an occult cancer, patients with these syndromes should undergo a diagnostic screening program for malignant disease.