[Experience of disease, relationship and sexuality in patients with COPD]. / Krankheitserleben, Partnerschaft und Sexualität bei Patienten mit COPD.

Experience of disease, relationship and sexuality in patients with COPD Objectives: We aimed to determine the impacts of chronic obstructive pulmonary disease (COPD) on the patient's relationship and sexuality. Methods: In a multicentric study 105, 52 of them female, non-selected COPD patients who were married or in a partnership were interviewed about their partnership and sexuality. Results: Average age was 64.1 ± 9.2 years. Patients with a more severe COPD had a lower Self-Illness-Separation (SIS), i. e. they reveal significantly higher burden of suffering. Life satisfaction and satisfaction with partnership, sexuality and sexual intercourse has decreased significantly since the diagnosis (p < 0.05). Desire and frequency to be sexually active have also decreased (p < 0.001). 61 % of the respondents felt increasingly dependent from their partner. Conclusion: The results underline that patients have a stage-dependent emotional distance to their illness, the partnership develops in direction of dependency, and sexuality deteriorates with increasing severity of the COPD. The PRISM test proved to be a great way to illustrate this development and to start a conversation with the patients about it. COPD patients and their partners should be referred to the potential impact of the disease on their partnership and sexuality and should be supported in their potential solutions considering gender-specific aspects.

The role of transketolase and octulose in the resurrection plant Craterostigma plantagineum.

Phylogenetic analysis revealed that Craterostigma plantagineum has two transketolase genes (transketolase 7 and 10) which are separated from the other transketolase genes including transketolase 3 from C. plantagineum We obtained recombinant transketolase 3, 7, and 10 of C. plantagineum and showed that transketolase 7 and 10 of C. plantagineum, but not transketolase 3, catalyse the formation of octulose-8-phosphate in vitro Transketolase 7 and 10 of C. plantagineum performed the exchange reaction that produces octulose-8-phosphate using glucose-6-phosphate and fructose-6-phosphate as substrates. Octulose is localized in the cytosol and phloem exudate analysis showed that octulose was the dominant sugar exported from the leaves to the roots.

Successful treatment of paraneoplastic hypercalcemia in a patient with giant condyloma acuminatum: a case report.

INTRODUCTION: While paraneoplastic syndromes in patients with malignant and metastasizing tumors are common, they are rarely associated with skin tumors showing predominantly local growth patterns. This case report relates to a patient with giant condyloma acuminatum, also called Buschke-Löwenstein tumor, with paraneoplastic hypercalcemia, who was successfully treated with conservative treatment. CASE PRESENTATION: The patient in question is a 48-year-old German man with a giant periscrotal tumor. Before and during the therapy, two episodes of symptomatic hypercalcemia occurred, which were successfully treated by bisphosphonates, intravenous fluids and diuretics. No evidence of lytic bone affection was found. CONCLUSIONS: Paraneoplastic hypercalcemia may occur in patients who have a Buschke-Löwenstein tumor. For patients, where surgery is not an option, established medical therapies like bisphosphonates may be useful in addition to diuretics and infusions.

Discovery of a cytokine and its receptor by functional screening of the extracellular proteome.

To understand the system of secreted proteins and receptors involved in cell-cell signaling, we produced a comprehensive set of recombinant secreted proteins and the extracellular domains of transmembrane proteins, which constitute most of the protein components of the extracellular space. Each protein was tested in a suite of assays that measured metabolic, growth, or transcriptional responses in diverse cell types. The pattern of responses across assays was analyzed for the degree of functional selectivity of each protein. One of the highly selective proteins was a previously undescribed ligand, designated interleukin-34 (IL-34), which stimulates monocyte viability but does not affect responses in a wide spectrum of other assays. In a separate functional screen, we used a collection of extracellular domains of transmembrane proteins to discover the receptor for IL-34, which was a known cytokine receptor, colony-stimulating factor 1 (also called macrophage colony-stimulating factor) receptor. This systematic approach is thus useful for discovering new ligands and receptors and assessing the functional selectivity of extracellular regulatory proteins.

Statins disrupt CCR5 and RANTES expression levels in CD4(+) T lymphocytes in vitro and preferentially decrease infection of R5 versus X4 HIV-1.

BACKGROUND: Statins have previously been shown to reduce the in vitro infection of human immunodeficiency virus type 1 (HIV-1) through modulation of Rho GTPase activity and lipid raft formation at the cell surface, as well as by disrupting LFA-1 incorporation into viral particles. PRINCIPLE FINDINGS: Here we demonstrate that treatment of an enriched CD4(+) lymphocyte population with lovastatin (Lov), mevastatin (Mev) and simvastatin (activated and non-activated, Sim(A) and Sim(N), respectively) can reduce the cell surface expression of the CC-chemokine receptor CCR5 (P<0.01 for Sim(A) and Lov). The lowered CCR5 expression was associated with down-regulation of CCR5 mRNA expression. The CC-chemokine RANTES protein and mRNA expression levels were slightly increased in CD4(+) enriched lymphocytes treated with statins. Both R5 and X4 HIV-1 were reduced for their infection of statin-treated cells; however, in cultures where statins were removed and where a decrease in CCR5 expression was observed, there was a preferential inhibition of infection with an R5 versus X4 virus. CONCLUSIONS: The results indicate that the modulation of CC-chemokine receptor (CCR5) and CC-chemokine (RANTES) expression levels should be considered as contributing to the anti-viral effects of statins, preferentially inhibiting R5 viruses. This observation, in combination with the immunomodulatory activity exerted by statins, suggests they may possess more potent anti-HIV-1 activity when applied during the early stages of infection or in lowering viral transmission. Alternatively, statin treatment could be considered as a way to modulate immune induction such as during vaccination protocols.

Intrapatient alterations in the human immunodeficiency virus type 1 gp120 V1V2 and V3 regions differentially modulate coreceptor usage, virus inhibition by CC/CXC chemokines, soluble CD4, and the b12 and 2G12 monoclonal antibodies.

We studied human immunodeficiency virus type 1 (HIV-1) chimeric viruses altering in their gp120 V1V2 and V3 envelope regions to better map which genetic alterations are associated with specific virus phenotypes associated with HIV-1 disease progression. The V1V2 and V3 regions studied were based on viruses isolated from an individual with progressing HIV-1 disease. Higher V3 charges were linked with CXCR4 usage, but only when considered within a specific V1V2 and V3 N-linked glycosylation context. When the virus gained R5X4 dual tropism, irrespective of its V3 charge, it became highly resistant to inhibition by RANTES and highly sensitive to inhibition by SDF-1alpha. R5 viruses with higher positive V3 charges were more sensitive to inhibition by RANTES, while R5X4 dualtropic viruses with higher positive V3 charges were more resistant to inhibition by SDF-1alpha. Loss of the V3 N-linked glycosylation event rendered the virus more resistant to inhibition by SDF-1alpha. The same alterations in the V1V2 and V3 regions influenced the extent to which the viruses were neutralized with soluble CD4, as well as monoclonal antibodies b12 and 2G12, but not monoclonal antibody 2F5. These results further identify a complex set of alterations within the V1V2 and V3 regions of HIV-1 that can be selected in the host via alterations of coreceptor usage, CC/CXC chemokine inhibition, CD4 binding, and antibody neutralization.

Anti-tumor immune responses and tumor regression induced with mimotopes of a tumor-associated T cell epitope.

Mimotopes provide an alternative to natural T cell epitopes for cancer immune therapy, as they can recruit and stimulate T cell repertoires that deviate from the repertoires engaged with the tumor and exposed to disease-related immune suppression. Here, mimotopes of a shared tumor-associated T cell epitope in cutaneous lymphoma were tested for their capacities to induce clinical and immunological responses in cancer patients. The mimotope sequences had been determined by a combinatorial peptide library approach without knowledge of the corresponding natural tumor-associated antigen. Vaccination with these mimotopes together with helper T cell-inducing antigens led to complete tumor remission in the two patients tested. After each booster vaccination, enhanced frequencies of mimotope-specific CD8+ T cells were detected in the peripheral blood of the patients, and the CTL proved to be cytotoxic and tumoricidal when tested in vitro. These data provide a first indication of clinical efficacy of mimotopes in cancer patients.

Subunit H of the V-ATPase binds to the medium chain of adaptor protein complex 2 and connects Nef to the endocytic machinery.

Nef is an accessory protein of human and simian immunodeficiency viruses (HIV and SIV) that is required for efficient viral infectivity and pathogenicity. It decreases the expression of CD4 on the surface of infected cells. V1H is the regulatory subunit H of the vacuolar membrane ATPase (V-ATPase). Previously, the interaction between Nef and V1H has been found to facilitate the internalization of CD4, suggesting that V1H could connect Nef to the endocytic machinery. In this study, we demonstrate that V1H binds to the C-terminal flexible loop in Nef from HIV-1 and to the medium chain (mu2) of the adaptor protein complex 2 (AP-2) in vitro and in vivo. The interaction sites of V1H and mu2 were mapped to a central region in V1H from positions 133 to 363, which contains 4 armadillo repeats, and to the N-terminal adaptin-binding domain in mu2 from positions 1 to 145. Fusing Nef to V1H reproduced the appropriate trafficking of Nef. This chimera internalized CD4 even in the absence of the C-terminal flexible loop in Nef. Finally, blocking the expression of V1H decreased the enhancement of virion infectivity by Nef. Thus, V1H can function as an adaptor for interactions between Nef and AP-2.

Interaction between Nef and phosphatidylinositol-3-kinase leads to activation of p21-activated kinase and increased production of HIV.

The negative factor (Nef) is one of six accessory proteins from primate lentiviruses (HIV-1, HIV-2, and SIV). It leads to high levels of viremia and the progression to AIDS in monkeys and humans. In this study, we demonstrated that Nef from HIV-1 binds to the regulatory subunit (p85) of phosphatidylinositol-3-kinase (PI3K). This interaction depended on the C-terminus of p85 and Nef. Moreover, PI3K was required to activate the Nef-associated p21-activated kinase (PAK). Finally, inhibition of PI3K blocked the activation of PAK and decreased the production of viral particles to levels observed with the Nef-deleted provirus. We conclude that Nef assembles a multiprotein signaling complex which is required for the optimal replication of HIV-1.

The activation of RalGDS can be achieved independently of its Ras binding domain. Implications of an activation mechanism in Ras effector specificity and signal distribution.

Small GTPases of the Ras family are major players of signal transduction in eukaryotic cells. They receive signals from a number of receptors and transmit them to a variety of effectors. The distribution of signals to different effector molecules allows for the generation of opposing effects like proliferation and differentiation. To understand the specificity of Ras signaling, we investigated the activation of RalGDS, one of the Ras effector proteins with guanine-nucleotide exchange factor activity for Ral. We determined the GTP level on RalA and showed that the highly conserved Ras binding domain (RBD) of RalGDS, which mediates association with Ras, is important but not sufficient to explain the stimulation of the exchange factor. Although a point mutation in the RBD of RalGDS, which abrogates binding to Ras, renders RalGDS independent to activated Ras, an artificially membrane-targeted version of RalGDS lacking its RBD could still be activated by Ras. The switch II region of Ras is involved in the activation, because the mutant Y64W in this region is impaired in the RalGDS activation. Furthermore, it is shown that Rap1, which was originally identified as a Ras antagonist, can block Ras-mediated RalGDS signaling only when RalGDS contains an intact RBD. In addition, kinetic studies of the complex formation between RalGDS-RBD and Ras suggest that the fast association between RalGDS and Ras, which is analogous to the Ras/Raf case, achieves signaling specificity. Conversely, the Ras x RalGDS complex has a short lifetime of 0.1 s and Rap1 forms a long-lived complex with RalGDS, possibly explaining its antagonistic effect on Ras.