Depression and anxiety in women with malignant ovarian germ cell (MOGCT) and sex cord stromal tumors (SCST): an analysis of the AGO-CORSETT database.

INTRODUCTION: The intention of this study was to evaluate the level of anxiety and depression of malignant ovarian germ cell (MOGCT) and sex cord stromal tumors (SCST) survivors and to identify possible alterable cofactors. METHODS: CORSETT was an observational, multicenter, mixed retrospective/prospective cohort study of the AGO Studygroup. Women who had been diagnosed with MOGCTs and SCSTs between 2001 and 2011 were asked to complete the Hospital Anxiety and Depression Scale (HADS) to evaluate distress. Predictors of distress (type of surgery, chemotherapy, time since diagnosis, recurrence, second tumor, pain) were investigated using multivariate linear regression analysis. RESULTS: 150 MOGCT and SCST patients with confirmed histological diagnosis completed the questionnaire median seven years after diagnosis. They had a HADS total score ≥ 13 indicating severe mental distress in 34% of cases. Patients after fertility-conserving surgery had lower probability of severe mental distress than those without fertility-conserving treatment (ß = - 3.1, p = 0.04). Pain was associated with the level of distress in uni- and multivariate analysis (coef 0.1, p < 0.01, coef. Beta 0.5). DISCUSSION: Severe mental distress was frequent in patients with MOGCT and SCST and the level of pain was associated with the level of distress. Fertility conserving therapy, however, was associated with less mental distress. Screening and treatment of pain and depression is required to improve mental well-being in survivors of MOGCT and SCST.

Disentangling functional trait variation and covariation in epiphytic lichens along a continent-wide latitudinal gradient.

Characterizing functional trait variation and covariation, and its drivers, is critical to understand the response of species to changing environmental conditions. Evolutionary and environmental factors determine how traits vary among and within species at multiple scales. However, disentangling their relative contribution is challenging and a comprehensive trait-environment framework addressing such questions is missing in lichens. We investigated the variation in nine traits related to photosynthetic performance, water use and nutrient acquisition applying phylogenetic comparative analyses in lichen epiphytic communities on beech across Europe. These poikilohydric organisms offer a valuable model owing to their inherent limitations to buffer contrasting environmental conditions. Photobiont type and growth form captured differences in certain physiological traits whose variation was largely determined by evolutionary processes (i.e. phylogenetic history), although the intraspecific component was non-negligible. Seasonal temperature fluctuations also had an impact on trait variation, while nitrogen content depended on photobiont type rather than nitrogen deposition. The inconsistency of trait covariation among and within species prevented establishing major resource use strategies in lichens. However, we did identify a general pattern related to the water-use strategy. Thus, to robustly unveil lichen responses under different climatic scenarios, it is necessary to incorporate both among and within-species trait variation and covariation.

Pharmacokinetics and pulmonary distribution of gamithromycin after intravenous administration in foals.

The long-acting azalide antibiotic gamithromycin is marketed for intramuscular treatment of bovine and swine infections. Off-label use in foals leads to severe local lesions likely caused by hyperosmolality of the injected solution. We provide evidence from a pharmacokinetic study in 10 warm-blooded healthy foals for intravenous bolus injection of gamithromycin diluted in distilled water to be a safe and well tolerated alternative. By intravenous dosing, markedly higher plasma exposure and better penetration into bronchoalveolar lavage cells but lower distribution into epithelial lining fluid are achieved as after intramuscular or subcutaneous administration. Intravenously injected gamithromycin was tolerated without any adverse drug reactions. The protocols for treatment of equine pulmonary infections caused by Rhodococcus equi should be revised accordingly.

[Psychiatric psychotherapeutic interventions in breast cancer inpatients: a contribution to liaison-consultation psychiatry]. / Psychiatrisch-psychotherapeutische Interventionen bei Mammakarzinompatientinnen : Ein Beitrag zur Konsiliarpsychiatrie.

BACKGROUND: Psychosocial stress and psychopathological abnormalities are expected in cancer patients at a frequency of 30-60%. Apart from decreased quality of life psychological factors may cause a negative impact on treatment compliance and on the subsequent biological course of tumor development. MATERIALS AND METHODS: This study examined the association of different psychiatric and psychotherapeutic interventions in liaison-consultation psychiatry with the four psychopathological dimensions derived by factor analysis based on the items of psycho-oncological basic documentation in a group of 141 breast cancer patients without pre-existing mental disorders who were inpatients of a gynecologic cancer centre. In addition information concerning subjective stress experience was collected with the distress thermometer. RESULTS: The plausible fit of the various psychiatric and psychotherapeutic interventions due to the psychopathological dimensions and due to the subjective experience of stress could be demonstrated. Those intervention variables that were associated with an improvement of the psychological state could be described as well. The findings showed that improvement or at least stability of the psychological state was regularly associated with completion of oncological treatment in the relevant index inpatient stay. In addition it was found that the interventions offered could contribute to improved psychological well-being in the subgroup of patients without mental disorders particularly in normal grief reactions. CONCLUSION: Despite methodological limitations this investigation contributes to describing relevant psychopathological syndromes in a group of breast cancer patients without pre-existing mental disorders and the goodness of fit of the different psychiatric and psychotherapeutic interventions. Finally the study confirmed the assumption that stabilization of the mental state may help to avoid treatment interruptions in an oncological inpatient setting and therefore decrease the likelihood that reduced psychological well-being can negatively impact the biological course of tumor development.

Case report: Sustained complete remission with all-oral MEPED therapy in a patient with Hodgkin's disease developing resistance to pembrolizumab.

Targeted chemotherapy and immune checkpoint inhibitors (ICPi) have expanded the spectrum of therapies for patients with relapsed/refractory (r/r) Hodgkin's disease and significantly improved the proportion of patients with long-term disease control. However, there is no standardized therapeutic option in case of further progression. Recently, we demonstrated that therapy with MEPED (metronomic chemotherapy, everolimus, pioglitazone, etoricoxib, dexamethasone) is highly effective in patients with r/r Hodgkin's disease. The benefit after pre-treatment with ICPi has not been studied, yet. Here, we report a patient with progressive Hodgkin's disease on Pembrolizumab for the first time who achieved sustained complete remission (CR) after initiation of MEPED therapy. A 57-year-old patient was pre-treated with brentuximab vedotin for relapsed advanced Hodgkin's disease and had received Pembrolizumab for progression from November 2020 to July 2022. Due to further progression, MEPED therapy was started in August 2022 and continued until May 2023. It consisted of a strictly oral daily (28-day cycle) application of low-dose treosulfan 250 mg, everolimus 15 mg, pioglitazone 45 mg, etoricoxib 60 mg, and dexamethasone 0.5 mg. Treatment response was evaluated by F-18 FDG-PET/CT (PET/CT). CR was defined by a negative Deauville score (DS) of 1-3. Already 3 months after starting MEPED, a CR (DS: 3) was confirmed by PET/CT in November 2022. The next follow-up in May 2023 continued to show CR (DS: 3). The therapy was very well tolerated. No hematological or other organ toxicity was observed. However, in May 2023 the patient presented with leg edema and weight gain, most likely due to pioglitazone and the PET/CT revealed suspected everolimus-induced pneumonitis, so MEPED was discontinued and diuretic therapy and treatment with prednisolone was started with gradual dose reduction. This resulted in a rapid complete resolution of the symptoms. The next PET-CT in July 2023 continued to show CR (DS: 3) without evidence of pneumonitis. Currently, therapy with MEPED has not been resumed. In conclusion, we demonstrate for the first time that MEPED therapy is highly effective in a patient with Hodgkin's disease who has been refractory to ICPi. Sustained CR was achieved over 11 months after initiation of MEPED therapy. Further studies on a larger patient cohort should be performed.

[Psychiatric disorders associated with imminent deportation. Results of a retrospective study in a group of immigrants]. / Psychiatrische Erkrankungen bei drohender Abschiebung. Ergebnisse einer retrospektiven Studie.

BACKGROUND: The aim of this study was to investigate characteristics of migrants facing imminent deportation in comparison with migrants with guaranteed residence status. The occurrence of psychoreactive disorders in both groups was examined. PATIENTS AND METHODS: In a case-control study 82 migrants recorded as inpatients facing imminent deportation were compared to a control group of 93 migrants with guaranteed residence status. RESULTS: Migrants facing imminent deportation more frequently suffered from psychoreactive disorders, compared to migrants with guaranteed residence status. In this subgroup psychoreactive disorders were associated with reported traumatisations. Imminent deportation within the next month was associated with the diagnosis of psychoreactive disorder as well. CONCLUSION: Psychoreactive disorders appeared more frequently in immigrant inpatients facing imminent deportation. Additionally a history of traumatisations is associated with the progression of psychoreactive disorders.

[Unusual skin alterations in a 72-year-old patient with multiple myeloma]. / Ungewöhnliche Hautveränderungen bei 72-jähriger Patientin mit multiplem Myelom.

We report on a 72-year-old female patient with multiple myeloma who presented with alopecia and eye-catching alterations of the skin and the nails. A biopsy of the skin could confirm the diagnosis of immunoglobulin light chain (AL) amyloidosis, which was also suspected of having affected other organs. After six cycles of a cytoreductive therapy with bortezomib and dexamethasone a very good partial response of the multiple myeloma was seen and an improvement in the skin and nail alterations could be achieved.

Fusarium and allied fusarioid taxa (FUSA). 1.

Seven Fusarium species complexes are treated, namely F. aywerte species complex (FASC) (two species), F. buharicum species complex (FBSC) (five species), F. burgessii species complex (FBURSC) (three species), F. camptoceras species complex (FCAMSC) (three species), F. chlamydosporum species complex (FCSC) (eight species), F. citricola species complex (FCCSC) (five species) and the F. concolor species complex (FCOSC) (four species). New species include Fusicolla elongata from soil (Zimbabwe), and Neocosmospora geoasparagicola from soil associated with Asparagus officinalis (Netherlands). New combinations include Neocosmospora akasia, N. awan, N. drepaniformis, N. duplosperma, N. geoasparagicola, N. mekan, N. papillata, N. variasi and N. warna. Newly validated taxa include Longinectria gen. nov., L. lagenoides, L. verticilliforme, Fusicolla gigas and Fusicolla guangxiensis. Furthermore, Fusarium rosicola is reduced to synonymy under N. brevis. Finally, the genome assemblies of Fusarium secorum (CBS 175.32), Microcera coccophila (CBS 310.34), Rectifusarium robinianum (CBS 430.91), Rugonectria rugulosa (CBS 126565), and Thelonectria blattea (CBS 952.68) are also announced here. Citation: Crous PW, Sandoval-Denis M, Costa MM, Groenewald JZ, van Iperen AL, Starink-Willemse M, Hernández-Restrepo M, Kandemir H, Ulaszewski B, de Boer W, Abdel-Azeem AM, Abdollahzadeh J, Akulov A, Bakhshi M, Bezerra JDP, Bhunjun CS, Câmara MPS, Chaverri P, Vieira WAS, Decock CA, Gaya E, Gené J, Guarro J, Gramaje D, Grube M, Gupta VK, Guarnaccia V, Hill R, Hirooka Y, Hyde KD, Jayawardena RS, Jeewon R, Jurjevic Z, Korsten L, Lamprecht SC, Lombard L, Maharachchikumbura SSN, Polizzi G, Rajeshkumar KC, Salgado-Salazar C, Shang Q-J, Shivas RG, Summerbell RC, Sun GY, Swart WJ, Tan YP, Vizzini A, Xia JW, Zare R, González CD, Iturriaga T, Savary O, Coton M, Coton E, Jany J-L, Liu C, Zeng Z-Q, Zhuang W-Y, Yu Z-H, Thines M (2022). Fusarium and allied fusarioid taxa (FUSA). 1. Fungal Systematics and Evolution 9: 161-200. doi: 10.3114/fuse.2022.09.08.

Patient state index vs bispectral index as measures of the electroencephalographic effects of propofol.

BACKGROUND: The patient state index (PSI) and the bispectral index (BIS) quantify anaesthetic depth based on the EEG using different algorithms. We compared both indices with regard to the prediction of the depth of propofol anaesthesia. METHODS: In 17 patients, propofol was infused until burst suppression occurred and stopped thereafter until BIS recovered to values above 60. This was repeated; afterwards, patients were intubated, for subsequent surgery. Without surgical stimulus, PSI and BIS were measured simultaneously and compared with the estimated effect-site concentrations of propofol. These were derived from simultaneous pharmacokinetic and -dynamic modelling in an individual two-stage and a population-based NONMEM approach. RESULTS: A close sigmoid relationship was observed between the propofol effect-site concentration and both PSI [coefficient of determination rho(2)=0.91 (sd 0.05)] and BIS [rho(2)=0.92 (0.03)], which was significantly steeper for PSI [gamma=2.2 (0.6)] than for BIS [gamma=1.8 (0.4)], and reached significantly lower values for PSI [E(max)=0.3 (1.1)] than for BIS [E(max)=5.3 (6.7)] at maximal propofol concentrations. A significantly smaller k(e0) was obtained for PSI [0.09 (0.03) min(-1)] compared with BIS [0.10 (0.02) min(-1)]. PSI and BIS correlated significantly with each other (rho(2)=0.866) and predicted propofol effect-site concentration with a comparable probability [P(K)=0.87 (0.05) and 0.86 (0.05), respectively]. NONMEM revealed E(0)=89.3 and 92.3, E(max)=1.9 and 8.6, C(e50)=1.38 and 1.92 microg ml(-1), gamma=1.6 and 1.48, and k(e0)=0.103 and 0.131 min(-1) as typical values for PSI and BIS, respectively. CONCLUSIONS: The PSI and the BIS monitors performed equally well in predicting depth of propofol anaesthesia. However, PSI was lower than BIS by approximately 10-15 points at high propofol concentrations.

Multiple origins of lichen symbioses in fungi suggested by SSU rDNA phylogeny.

Phylogenetic hypotheses provide a context for examining the evolution of heterotrophic lifestyles. The lichen lifestyle, which is the symbiotic association of fungi with algae, is found in various representatives of Dicaryomycotina, both Ascomycetes and Basidiomycetes. A highly resolved parsimony analysis of small subunit ribosomal DNA (SSU rDNA) sequences suggests at least five independent origins of the lichen habit in disparate groups of Ascomycetes and Basidiomycetes. Because lichen associations arose from parasitic, mycorrhizal, or free-living saprobic fungi, neither mutualism nor parasitism should be construed as endpoints in symbiont evolution.

Black fungi in lichens from seasonally arid habitats.

We present a phylogenetic study of black fungi in lichens, primarily focusing on saxicolous samples from seasonally arid habitats in Armenia, but also with examples from other sites. Culturable strains of lichen-associated black fungi were obtained by isolation from surface-washed lichen material. Determination is based on ITS rDNA sequence data and comparison with published sequences from other sources. The genera Capnobotryella, Cladophialophora, Coniosporium, Mycosphaerella, and Rhinocladiella were found in different lichen species, which showed no pathogenic symptoms. A clade of predominantly lichen-associated strains is present only in Rhinocladiella, whereas samples of the remaining genera were grouped more clearly in clades with species from other sources. The ecology of most-closely related strains indicates that Capnobotryella and Coniosporium, and perhaps also Rhinocladiella strains opportunistically colonise lichens. In contrast, high sequence divergence in strains assigned to Mycosphaerella could indicate the presence of several lichen-specific species with unknown range of hosts or habitats, which are distantly related to plant-inhabitants. Similar applies to Cladophialophora strains, where the closest relatives of the strains from lichens are serious human pathogens.

Intestinal and hepatic contributions to the pharmacokinetic interaction between gamithromycin and rifampicin after single-dose and multiple-dose administration in healthy foals.

BACKGROUND: Standard treatment of foals with severe abscessing lung infection caused by Rhodococcus equi using rifampicin and a macrolide antibiotic can be compromised by extensive inhibition and/or induction of drug metabolising enzymes (e.g. CYP3A4) and transport proteins (e.g. P-glycoprotein), as has been shown for rifampicin and clarithromycin. The combination of rifampicin with the new, poorly metabolised gamithromycin, a long-acting analogue of azithromycin and tulathromycin with lower pharmacokinetic interaction potential, might be a suitable alternative. OBJECTIVES: To evaluate the pharmacokinetic interactions and pulmonary distribution of rifampicin and gamithromycin in healthy foals, and to investigate the cellular uptake of gamithromycin in vitro. STUDY DESIGN: Controlled, four-period, consecutive, single-dose and multiple-dose study. METHODS: Pharmacokinetics and lung distribution of rifampicin (10 mg/kg) and gamithromycin (6 mg/kg) were measured in nine healthy foals using LC-MS/MS. Enzyme induction was confirmed using the 4ß-OH-cholesterol/cholesterol ratio. Affinity of gamithromycin to drug transport proteins was evaluated in vitro using equine hepatocytes and MDCKII-cells stably transfected with human OATP1B1, OATP1B3 and OATP2B1. RESULTS: Rifampicin significantly (P<0.05) increased the plasma exposure of gamithromycin (16.2 ± 4.77 vs. 8.57 ± 3.10 µg × h/mL) by decreasing the total body clearance. Otherwise, gamithromycin significantly lowered plasma exposure of single- and multiple-dose rifampicin (83.8 ± 35.3 and 112 ± 43.1 vs. 164 ± 96.7 µg × h/mL) without a change in metabolic ratio and half-life. Gamithromycin was identified as an inhibitor of human OATP1B1, OATP1B3 and OATP2B1 and as a substrate of OATP2B1. In addition, it was extracted by equine hepatocytes via a mechanism which could be inhibited by rifampicin. MAIN LIMITATIONS: Influence of gamithromycin on pulmonary distribution of rifampicin was not evaluated. CONCLUSION: The plasma exposure of gamithromycin is significantly increased by co-administration of rifampicin which is most likely caused by inhibition of hepatic elimination.

[POEMS syndrome as a rare cause of bilateral optic disc edema]. / POEMS-Syndrom als seltene Ursache eines bilateralen Papillenödems.

The POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, skin changes) is a rare paraneoplastic syndrome based on a clonal plasma cell disorder. Optic disc edema (ODE) is a frequent ocular sign in POEMS syndrome. The cause of the ODE has not yet been entirely clarified. This article reports the case of a 62-year-old male suffering from POEMS syndrome with a bilateral ODE.

Pharmacological indices and pulmonary distribution of rifampicin after repeated oral administration in healthy foals.

BACKGROUND: The treatment of equine lung infections by Rhodococcus equi with rifampicin is empirically based because pharmacokinetic/pharmacodynamic (PK/PD) indices and pivotal clinical outcome data are not available. OBJECTIVES: To evaluate the pharmacokinetics and pulmonary distribution of rifampicin into epithelial lining fluid (ELF) and bronchoalveolar lavage cells (BALC) to predict antimicrobial activity in the lung using PK/PD indices. STUDY DESIGN: Controlled, randomised, two-period, crossover, repeated-dose study with an initial arm to measure disposition after i.v. administration of rifampicin. METHODS: Pharmacokinetics and lung distribution were evaluated in six healthy foals treated with 10 mg/kg bwt rifampicin i.v. (initial arm) and with repeated oral doses of rifampicin at 10 mg/kg bwt and 20 mg/kg bwt once per day for 10 days (crossover arms). ELF and BALC were sampled by bronchoalveolar lavage 24 h after the last oral dosing. Rifampicin and 25-O-desacetyl rifampicin were quantified using liquid chromatography tandem-mass spectrometry. Enzyme induction by rifampicin was confirmed by evaluation of plasma 4ß-OH-cholesterol:cholesterol ratios. RESULTS: The distribution volume of rifampicin administered i.v. was ~0.85 L/kg. Terminal elimination half-life was ~11 h. Orally given rifampicin was slowly absorbed (Tmax , range: 2.5-8.0 h) and eliminated with apparent half-lives of ~6-8 h. Trough concentrations in ELF and BALC were 1.01 ± 0.20 µg/mL and 1.25 ± 0.29 µg/mL, respectively, after 10 mg/kg bwt rifampicin and 2.71 ± 1.25 µg/mL and 3.09 ± 1.63 µg/mL, respectively, after 20 mg/kg bwt rifampicin. The average ratios of area under the plasma concentration time curve during an administration interval of 24 h (AUC0-24 h ) to minimum inhibitory concentration (MIC) were 145 and 322 h, respectively, for less susceptible strains of R. equi (MIC90 : 0.5 µg/mL). MAIN LIMITATIONS: The clearance and bioavailability of rifampicin after repeated oral dosing were not evaluated. CONCLUSIONS: Treatment with rifampicin at 10 mg/kg bwt administered once per day is suitable to generate drug concentrations above the MIC90 in the ELF and BALC of foals. Future clinical studies with rifampicin in combination with macrolide antibiotics with low drug interaction potential are required to translate the PK/PD indices into protocols for the treatment of R. equi lung infections.

Evidence for causal top-down frontal contributions to predictive processes in speech perception.

Perception relies on the integration of sensory information and prior expectations. Here we show that selective neurodegeneration of human frontal speech regions results in delayed reconciliation of predictions in temporal cortex. These temporal regions were not atrophic, displayed normal evoked magnetic and electrical power, and preserved neural sensitivity to manipulations of sensory detail. Frontal neurodegeneration does not prevent the perceptual effects of contextual information; instead, prior expectations are applied inflexibly. The precision of predictions correlates with beta power, in line with theoretical models of the neural instantiation of predictive coding. Fronto-temporal interactions are enhanced while participants reconcile prior predictions with degraded sensory signals. Excessively precise predictions can explain several challenging phenomena in frontal aphasias, including agrammatism and subjective difficulties with speech perception. This work demonstrates that higher-level frontal mechanisms for cognitive and behavioural flexibility make a causal functional contribution to the hierarchical generative models underlying speech perception.

Differential regulation of transport proteins in the periinfarct region following reversible middle cerebral artery occlusion in rats.

Members of various transport protein families including ATP-binding cassette transporters and solute carriers were shown to be expressed in brain capillaries, choroid plexus, astrocytes or neurons, controlling drug and metabolite distribution to and from the brain. However, data are currently very limited on how the expression of these transport systems is affected by damage to the brain such as stroke. Therefore we studied the expression of four selected transporters, P-glycoprotein (Mdr1a/b; Abcb1a/b), Mrp5 (Abcc5), Bcrp (Abcg2), and Oatp2 (Slc21a5) in a rat model for stroke. Transporter expression was analyzed by real-time polymerase chain reaction in the periinfarcted region and protein localization and cellular phenotyping were done by immunohistochemistry and confocal immunofluorescence microscopy. After stroke, P-glycoprotein staining was detected in endothelial cells of disintegrated capillaries and by day 14 in newly generated blood vessels. There was no significant difference, however, in the Mdr1a mRNA amount in the periinfarcted region compared with the contralateral site. For Bcrp, a significant mRNA up-regulation was observed from days 3-14. This up-regulation was followed by the protein as confirmed by quantitative immunohistochemistry. Oatp2, located in the vascular endothelium, was also up-regulated at day 14. For Mrp5, an up-regulation was observed in neurons in the periinfarcted region (day 14). In conclusion, after stroke the transport proteins were up-regulated with a maximum at day 14, a time point that coincides with behavioral recuperation. The study further suggests Bcrp as a pronounced marker for the regenerative process and a possible functional role of Mrp5 in surviving neurons.

Phenotype and function of a CD56+ peripheral blood monocyte.

G-CSF primed CD34 cells cultured for 2-3 weeks in IL-2 and stem cell factor generate CD56(high) cells with phenotypic and morphologic features of NK cells, and a novel adherent CD56(low) CD16- population expressing myeloid markers (CD33 and HLA-DR). We hypothesized that similar cells might also occur in peripheral blood. In 13/13 normal individuals, we found a circulating population of CD56(low), CD33+, FcgammaRI+, FcgammaRII+, HLA-DR+, CD11b(high), CD14+ monocytes closely resembling the cultured CD56(low)CD33+ cells. They may represent a normal counterpart of the CD56+ CD33+ hybrid myeloid/natural killer cell leukemia. Their mean frequency was 1.3+/-1% (standard deviation), range 0.16-3.5%, of total mononuclear cells. CD56(low)CD33+ cells, primed with cytomegalovirus antigen, induced autologous T-lymphocyte proliferation comparably to CD56-, CD14+ peripheral blood monocytes (PBM). Conversely, CD56(low) cells induced greater T-cell proliferation than CD56- PBM when lymphocyte responders were HLA mismatched. Unstimulated CD56(low)CD33+ cells showed a low antiproliferative effect on K562, which was increased upon LPS stimulation. The pattern of cytokine production by CD56(low)CD33+ cells and PBM largely overlapped; however, they produced detectable levels of IL-6 and IL-1beta. These results define a minor monocyte population with distinct phenotypic and functional features.

Verapamil regulates activity and mRNA-expression of human beta-glucuronidase in HepG2 cells.

A promising development in tumor therapy is the application of non-toxic prodrugs from which the active cytostatic is released by endogenous enzymes such as beta-glucuronidase (beta-gluc). Regulation of beta-gluc expression is one crucial factor modulating bioactivation of prodrugs. Recent experiments in rats indicate regulation of beta-gluc activity by the calcium channel blocker verapamil. To further explore this phenomenon, we investigated the effect of verapamil on beta-gluc enzyme activity, protein (western blot) and mRNA expression (RT-PCR) as well as the underlying mechanisms (effects of verapamil metabolites; promoter activity) in the human hepatoma cell line HepG2. Treatment of HepG2 cells with verapamil revealed down-regulation of beta-gluc activity, protein, and mRNA level down to 50% of the control with EC(50) values of 25 microM. Effects were similar for both enantiomers. Moreover, it was demonstrated that reduced promoter activity contributes to the observed effects. In summary, our data demonstrate regulation of human beta-glucuronidase expression by verapamil. Based on our findings we hypothesize that coadministration of verapamil may effect cleavage of glucuronides by beta-glucuronidase.

Positioning against niche competitors to reduce revenue erosion.

Health care providers around the country face a growing threat from more limited service "niche" providers, often sponsored by specialty physicians. Mark Grube, vice president of Abendshien+Grube Associates, writes that hospitals and health systems may want to consider joint ventures with physicians to counter this trend.