[Quality of patient information leaflets on atopic eczema : An analysis using the DISCERN instrument]. / Qualität von Patienteninformationsbroschüren zum atopischen Ekzem : Eine Analyse mithilfe des DISCERN-Instruments.

BACKGROUND: As in other chronic diseases, providing medical information plays a key role in the therapy of atopic eczema. It is already known that information leaflets often do not meet the criteria of evidence-based patient information (EBPI). OBJECTIVE: Therefore, the aim of this study was to examine the quality of information leaflets on atopic eczema. MATERIAL AND METHODS: A total of 35 leaflets were included in the study. They were collected from self-aid groups, from the internet, from general practitioners, from pediatricians and dermatologists as well as from pharmacies in Regensburg. The quality of information provided was assessed using the DISCERN instrument. RESULTS: Almost all of the 35 patient information leaflets assessed had shortcomings, scoring only mid- or low-point in the analysis. None of the leaflets was of excellent quality. Only three leaflets were estimated to contain good quality information. CONCLUSION: Most of the leaflets did not meet the criteria of evidence-based patient information. In conclusion, there may be a lack of quality information about atopic eczema. Improving the existing material and comparing the EBPI standards with the information needs of atopic eczema patients should be topics of future research.

Efficacy and safety of 12 weeks of elbasvir ± grazoprevir ± ribavirin in participants with hepatitis C virus genotype 2, 4, 5 or 6 infection: The C-SCAPE study.

People with hepatitis C virus (HCV) infection other than genotype 1 represent a heterogeneous group. The aim of the phase 2 C-SCAPE study was to evaluate elbasvir/grazoprevir (EBR/GZR), with or without ribavirin (RBV), in participants with HCV genotype 2, 4, 5 or 6 infection. This was a part randomised, open-label, parallel-group study (NCT01932762; PN047-03) of treatment-naive, noncirrhotic participants. Participants with HCV genotype 2 infection received GZR 100 mg + RBV ± EBR 50 mg for 12 weeks and those with genotype 4, 5 or 6 infection were randomized to receive EBR/GZR ± RBV for 12 weeks. The primary endpoint was sustained virological response 12 weeks after completion of treatment (SVR12; HCV RNA <25 IU/mL). Among participants with genotype 2 infection, SVR12 was achieved by 80% (24/30) of those receiving EBR/GZR + RBV and 73% (19/26) of those receiving GZR + RBV. SVR rates were high in participants with HCV genotype 4 infection receiving EBR/GZR with and without RBV (100% [10/10] and 90% [9/10]; respectively). In contrast, the addition of RBV to EBR/GZR appeared to increase SVR12 in participants with genotype 5 infection (EBR/GZR, 25%; EBR/GZR + RBV 100% [4/4]). In participants with genotype 6 infection, SVR12 was 75% (3/4) in both those receiving EBR/GZR and those receiving EBR/GZR + RBV. The safety profile was similar across treatment arms, with adverse events tending to occur more frequently among participants receiving RBV. In conclusion, these data support the inclusion of participants with genotype 4 or 6 infection in the EBR/GZR phase 3 studies. EBR/GZR ± RBV was unsatisfactory for participants with genotype 2 or 5 infection.

A novel BCMA/CD3 bispecific T-cell engager for the treatment of multiple myeloma induces selective lysis in vitro and in vivo.

This corrects the article DOI: 10.1038/leu.2016.388.

Efficacy of 12 or 18 weeks of elbasvir plus grazoprevir with ribavirin in treatment-naïve, noncirrhotic HCV genotype 3-infected patients.

Elbasvir (EBR; HCV NS5A inhibitor) and grazoprevir (GZR; HCV NS3/4A protease inhibitor) are approved as a fixed-dose combination to treat patients chronically infected with HCV genotypes 1 and 4. During the development programme and supported by in vitro potency, the efficacy of EBR+GZR was assessed in HCV GT3-infected patients. This study's aim was to determine the efficacy and tolerability of 12 or 18 weeks of EBR+GZR with ribavirin (RBV) in treatment-naïve, noncirrhotic HCV GT3-infected patients. Randomized patients received open-label EBR (50 mg once daily) + GZR (100 mg once daily) + RBV. The primary efficacy objective was to evaluate the sustained virologic response rates 12 weeks after the end of all study therapy (SVR12). SVR12 rates (95% confidence interval) were 45.0% (23.1, 68.5) and 57.1% (34.0, 78.2) after treatment with EBR+GZR+RBV for 12 weeks or 18 weeks, respectively. On-treatment virologic failure was observed in 41% (17 of 41) of patients. At virologic failure, resistance-associated substitutions (RASs) with a >five-fold shift in potency occurred in the NS3 region in six (35%) patients and in the NS5A region in 16 (94%) patients. The most common RAS at virologic failure was Y93H in NS5A which was identified in 13 of 17 (76%) patients. The efficacy of EBR+GZR+RBV was suboptimal in HCV GT3-infected patients due to a high rate of on-treatment virologic failure and treatment-emergent RASs which demonstrates an inadequate barrier to the development of GT3 resistance. However, rapid viral clearance demonstrated the antiviral activity of EBR+GZR+RBV in GT3-infected patients.clinicaltrials.gov: NCT01717326.

A novel BCMA/CD3 bispecific T-cell engager for the treatment of multiple myeloma induces selective lysis in vitro and in vivo.

B-cell maturation antigen (BCMA) is a highly plasma cell-selective protein that is expressed on malignant plasma cells of multiple myeloma (MM) patients and therefore is an ideal target for T-cell redirecting therapies. We developed a bispecific T-cell engager (BiTE) targeting BCMA and CD3ɛ (BI 836909) and studied its therapeutic impacts on MM. BI 836909 induced selective lysis of BCMA-positive MM cells, activation of T cells, release of cytokines and T-cell proliferation; whereas BCMA-negative cells were not affected. Activity of BI 836909 was not influenced by the presence of bone marrow stromal cells, soluble BCMA or a proliferation-inducing ligand (APRIL). In ex vivo assays, BI 836909 induced potent autologous MM cell lysis in both, newly diagnosed and relapsed/refractory patient samples. In mouse xenograft studies, BI 836909 induced tumor cell depletion in a subcutaneous NCI-H929 xenograft model and prolonged survival in an orthotopic L-363 xenograft model. In a cynomolgus monkey study, administration of BI 836909 led to depletion of BCMA-positive plasma cells in the bone marrow. Taken together, these results show that BI 836909 is a highly potent and efficacious approach to selectively deplete BCMA-positive MM cells and represents a novel immunotherapeutic for the treatment of MM.

Efficacy and safety of grazoprevir + ribavirin for 12 or 24 weeks in treatment-naïve patients with hepatitis C virus genotype 1 infection.

Grazoprevir (GZR) is a second-generation hepatitis C virus NS3/4A protease inhibitor. The aim of this study was to evaluate GZR plus ribavirin (RBV) in patients with HCV GT1 infection. Noncirrhotic, IL28B CC patients with HCV genotype 1 infection were randomized to GZR 100 mg once daily and RBV for 12 or 24 weeks. Patients in the 12-week arm with detectable HCV RNA at treatment week 4 (TW4) had treatment extended to 24 weeks (response-guided therapy, RGT). The primary endpoint was sustained virologic response (SVR12) at follow-up week 12 (HCV RNA <25 IU/mL) in the per-protocol (PP) population (excluding patients with important protocol deviations). Twenty-six patients were randomized and 22 were included in the PP population. SVR12 was 58.3% (7 of 12) and 90% (9 of 10) in the RGT and 24-week arms, respectively. Seven PP patients had virologic failure, including one patient in the 24-week arm who relapsed after follow-up week 12. All three breakthrough patients had wild-type (WT) virus at baseline and developed breakthrough at TW6 or TW12 with Y56H, A156T and D168A/N mutations. Of the five relapse patients, four had WT at baseline (at relapse three had WT and one had V55A and D168A), and one had S122A/T at baseline and S122T at relapse. There were no serious adverse events (AEs), discontinuations due to AEs or grade 3/4 elevations in total and/or direct bilirubin. Grazoprevir plus RBV was associated with a rapid and sustained suppression of HCV RNA. These results support further evaluation of grazoprevir-based regimens (NCT01716156; protocol P039).

Grazoprevir plus peginterferon and ribavirin in treatment-naive patients with hepatitis C virus genotype 1 infection: a randomized trial.

UNLABELLED: Grazoprevir (MK-5172, Merck & Co., Inc.) is a selective inhibitor of the hepatitis C virus (HCV) NS3/4a protease. The aim of this study was to evaluate the safety and efficacy of grazoprevir at doses of 25-100 mg/day in combination with peginterferon and ribavirin (PEG-IFN/RBV). In this randomized, dose-ranging, multicentre trial, treatment-naive adults with chronic HCV genotype 1 infection received once-daily grazoprevir 25 mg, 50 mg or 100 mg plus PEG-IFN/RBV for 12 weeks. Patients with quantifiable HCV RNA (≥25 IU/mL) at week 4 received an additional 12 weeks of PEG-IFN/RBV. The primary endpoint was sustained virologic response (HCV RNA <25 IU/mL 12 weeks after completing therapy [SVR12]). Eighty-seven patients were randomly assigned and received ≥1 dose of therapy. Median time to undetectable HCV RNA was 16 days in the 100-mg arm and 22 days in the 25- and 50-mg arms. All patients except one had HCV RNA undetectable or unquantifiable at week 4 and received 12 weeks of therapy. SVR12 was achieved by 13 of 24 (54.2%), 21 of 25 (84.0%) and 23 of 26 (88.5%) patients in the 25-, 50- and 100-mg arms, respectively (per-protocol analysis). Three patients discontinued as a result of nonserious adverse events (AEs) and three patients experienced serious AEs. Transaminase elevations occurred in two patients (one each in the 25- and 100-mg arms). CONCLUSION: These data support further study of the grazoprevir 100-mg dose. Phase 3 studies of grazoprevir 100 mg in combination with elbasvir are currently ongoing (NCT01710501; protocol P038).

Ultrafast coherent oscillations reveal a reactive mode in the ring-opening reaction of fulgides.

The ultrafast ring-opening reaction of photochromic fulgides proceeds via conical intersections to the ground state isomers involving activation barriers in the excited state. The coherent oscillations observed in the femtosecond transient absorption signal of a methyl-substituted indolylfulgide were analysed in the framework of vibrational wavepackets to expose a dominant low-frequency mode at ∼80 cm(-1). The quantum chemical calculations in the relaxed excited state geometry of this fulgide revealed that the experimentally observed vibrational normal mode has a dominant contribution to the relevant ring-opening reactive coordinate.

Coherent exciton transport driven by torsional dynamics: a quantum dynamical study of phenylene-vinylene type conjugated systems.

We present a quantum dynamical study of exciton transfer across a torsional defect that locally breaks the pi-conjugation in an oligo-(p-phenylene vinylene) (OPV) fragment. A site-based vibronic coupling Hamiltonian is used which is formulated in a comparative fashion (i) for a Frenkel exciton basis, assuming localized electron-hole pairs whose superposition yields a delocalized exciton, and (ii) more accurately, for a Merrifield type exciton basis including spatially separated electron-hole pairs. Starting from a partially delocalized ("spectroscopic unit") initial condition, the observed transfer dynamics is found to involve two characteristic time scales: (i) a very rapid, coherent transient on a 10-100 femtosecond scale, largely determined by Rabi type oscillations modulated by bond-length-alternation modes, and (ii) a slower time scale involving the planarization of the torsional coordinates that determines the onset of a quasi-stationary exciton-polaron state, and in the process leads to a "healing" of the torsional defect within - 500 femtoseconds. The dynamics obtained from the full electron-hole basis vs. Frenkel basis are in good agreement. In the full electron-hole dynamics, the transients are found to involve a rapid expansion and subsequent contraction of the electron-hole coherence size. Quantum dynamical simulations for a minimal six-site model involving 36 states and 22 vibrational modes, were carried out using the multiconfiguration time dependent Hartree (MCTDH) method.

Soil mesofauna as bioindicators to assess environmental disturbance at a platinum mine in South Africa.

South Africa is rich in mineral resources and is one of the leading raw material exporters in the world. Mining is essential for economic development, but also has detrimental environmental consequences in the form of chemical waste products which are being dumped as tailings material. The aim of this study was to establish whether mesofauna could be utilized to assess the influence of the tailings disposal facility on the surrounding soil environment. The sampled soil was chemically analyzed and the extracted mesofauna identified. High metal concentrations on the tailings dam (Cu, Cr and Ni), apparently had the greatest influence on the soil mesofauna. Only a few mite species were abundant at the two sites on the tailings dam, representing the prostigmatic-, cryptostigmatic- and the mesostigmatic-taxa. Metal pollution is evident in the sites on the tailings dam facility and the number of species generally increased towards the more natural environment.

Graveyards - special landfills.

Graveyards have been a matter of controversial debate for many years in terms of the risk they pose to the environment. However, literature data are inconclusive and there are no systematic studies available from modern graveyards with special reference to soil found in the vicinity of the coffin. To our knowledge, the present study is the first to systematically investigate a comprehensive exhumation series (involving 40 graves) in order to determine burial-related changes in matter and element content. Human burials lead to the accumulation of certain elements, with higher than normal levels of N, C, Zn, Ba, Ca and Na being observed in soils below coffins. Decomposition material inside coffins has much higher levels of heavy metals and alkaline elements than the surrounding soil. However, the major problem observed was the large quantity of synthetic bedding material which is more likely to lead to the formation of adipocere under the moist conditions given. Adipocere formation, which is the result of the anaerobic bacterial hydrolysis of fat, is known to interrupt the natural decomposition process and delay the post-mortem release of elements. We assume that once the inhumed matter has completely decomposed, much higher than normal levels of pollutants will be released into and have an ecological effect on the soil and water environment.

A role for caveolin-1 in desmoglein binding and desmosome dynamics.

Desmoglein-2 (Dsg2) is a desmosomal cadherin that is aberrantly expressed in human skin carcinomas. In addition to its well-known role in mediating intercellular desmosomal adhesion, Dsg2 regulates mitogenic signaling that may promote cancer development and progression. However, the mechanisms by which Dsg2 activates these signaling pathways and the relative contribution of its signaling and adhesion functions in tumor progression are poorly understood. In this study we show that Dsg2 associates with caveolin-1 (Cav-1), the major protein of specialized membrane microdomains called caveolae, which functions in both membrane protein turnover and intracellular signaling. Sequence analysis revealed that Dsg2 contains a putative Cav-1-binding motif. A permeable competing peptide resembling the Cav-1 scaffolding domain bound to Dsg2, disrupted normal Dsg2 staining and interfered with the integrity of epithelial sheets in vitro. Additionally, we observed that Dsg2 is proteolytically processed; resulting in a 95-kDa ectodomain shed product and a 65-kDa membrane-spanning fragment, the latter of which localizes to lipid rafts along with full-length Dsg2. Disruption of lipid rafts shifted Dsg2 to the non-raft fractions, leading to the accumulation of these proteins. Interestingly, Dsg2 proteolytic products are elevated in vivo in skin tumors from transgenic mice overexpressing Dsg2. Collectively, these data are consistent with the possibility that accumulation of truncated Dsg2 protein interferes with desmosome assembly and/or maintenance to disrupt cell-cell adhesion. Furthermore, the association of Dsg2 with Cav-1 may provide a mechanism for regulating mitogenic signaling and modulating the cell-surface presentation of an important adhesion molecule, both of which could contribute to malignant transformation and tumor progression.

[Arguments for prophylactic therapy of ocular hypertension]. / Argumente für eine prophylaktische Therapie der okulären Hypertension.

Increased intraocular pressure is currently the only manipulable risk factor for glaucoma. In ocular hypertension the intraocular pressure is increased but the optic nerve head and visual field are thought to show no damage. Classification into glaucoma by means of the optic nerve head is often possible only over a period of time because there is a large overlap between the already pathological and still normal findings. In the Ocular Hypertension Treatment Study (OHTS) the effectiveness of prophylactic treatment was demonstrated. In the OHTS and the European Glaucoma Prevention Study (EGPS) risk factors have been identified, such as increased intraocular pressure, size of the excavation of the optic nerve head, decreased central corneal thickness, increased pattern standard deviation in the visual field and age. Before treatment of ocular hypertension is initiated these risk factors and the patient's personal situation should be considered. The higher the intraocular pressure, the smaller the central corneal thickness and the larger the excavation of the optic nerve and the younger the patient, the earlier treatment should be started.

Management and outcomes after multiple corneal and solid organ transplantations from a donor infected with rabies virus.

BACKGROUND: This article describes multiple transmissions of rabies via transplanted solid organ from a single infected donor. The empirical Milwaukee treatment regimen was used in the recipients. METHODS: Symptomatic patients were treated by deep sedation (ketamine, midazolam, and phenobarbital), ribavirin, interferon, and active and passive vaccination. Viral loads and antibodies were continuously monitored. RESULTS: Recipients of both cornea and liver transplants developed no symptoms. The recipient of the liver transplant had been vaccinated approximately 20 years before transplantation. Two recipients of kidney and lung transplants developed rabies and died within days of symptomatic disease. Another kidney recipient was treated 7 weeks before he died. The cerebrospinal fluid viral load remained at constant low levels (<10,000 copies/mL) for approximately 5 weeks; it increased suddenly by almost 5 orders of magnitude thereafter. After death, no virus was found in peripheral compartments (nerve tissue, heart, liver, or the small intestine) in this patient, in contrast to in patients in the same cohort who died early. CONCLUSIONS: Our report includes, to our knowledge, the longest documented treatment course of symptomatic rabies and the first time that the virus concentration was measured over time and in different body compartments. The postmortem virus concentration in the periphery was low, but there was no evidence of a reduction of virus in the brain.

Prevalence of deafness in dogs heterozygous or homozygous for the merle allele.

BACKGROUND: Deafness in dogs is frequently associated with the pigment genes piebald and merle. Little is known about the prevalence of deafness in dogs carrying the merle allele. OBJECTIVE: To determine the prevalence of deafness in dogs heterozygous and homozygous for the merle allele of the mouse Silver pigment locus homolog (SILV) gene. ANIMALS: One hundred and fifty-three privately owned merle dogs of different breeds and both sexes. METHODS: Hearing was tested by brainstem auditory-evoked response and classified as bilaterally hearing, unilaterally deaf, or bilaterally deaf. DNA from buccal cells was genotyped as either heterozygous or homozygous for the merle allele. Deafness association tests among merle genotype, eye color, and sex were performed by the chi(2) test. RESULTS: Deafness prevalence in merles overall was 4.6% unilaterally deaf and 4.6% bilaterally deaf. There was a significant association between hearing status and heterozygous versus homozygous merle genotype. For single merles (Mm), 2.7% were unilaterally deaf and 0.9% were bilaterally deaf. For double merles (MM), 10% were unilaterally deaf and 15% were bilaterally deaf. There was no significant association with eye color or sex. CONCLUSIONS: Deafness prevalence in merle dogs was greater than that in some dog breeds homozygous for the piebald gene, such as the English Cocker Spaniel, but comparable to, or lower than, that in the Dalmatian and white Bull Terrier. Dogs homozygous for the merle allele were significantly more likely to be deaf than heterozygotes.

Targeted release of oncolytic measles virus by blood outgrowth endothelial cells in situ inhibits orthotopic gliomas.

Malignant gliomas remain largely incurable despite intensive efforts to develop novel therapies. Replicating oncolytic viruses have shown great promise, among them attenuated measles viruses of the Edmonston B strain (MV-Edm). However, host immune response and the infiltrative nature of gliomas limit their efficacy. We show that human blood outgrowth endothelial cells (BOECs), readily expandable from peripheral blood, are easily infected by MV-Edm and allow replication of MV-Edm while surviving long enough after infection to serve as vehicles for MV-Edm (BOEC/MV-Edm). After intravenous and peritumoral injection, BOEC/MV-Edm deliver the viruses selectively to irradiated orthotopic U87 gliomas in mice. At the tumor, MV-Edm produced by the BOECs infect glioma cells. Subsequent spread from tumor cell to tumor cell leads to focal infection and cytopathic effects that decrease tumor size and, in the case of peritumoral injection, prolong survival of mice. Since MV-Edm within BOECs are not readily neutralized and because BOEC/MV-Edm search and destroy glioma cells, BOEC/MV-Edm constitute a promising novel approach for glioma therapy.

[Tumour stem cells--a new concept in tumour biology]. / Tumorstammzellen--ein neues Konzept in der Tumorbiologie.

There is growing evidence that tumours display a hierarchy similar to normal tissues. Accordingly, a small population of tumour stem cells is supposed to perpetuate tumour growth. These cells renew themselves and are highly tumourigenic upon injection into immunocompromised animals, yielding tumours largely identical to those from which they were derived. Tumour stem cells exhibit a high degree of chemoresistance due to slow cycling and constitutive expression of multiple members of the ATP-BINDING CASSETTE (ABC) family of transporters. An increasing number of tumours with tumour stem cells has been identified by now, including breast, brain, colon and prostate cancers, as well as leukemias. Detailed characterization of tumour stem cells may contribute to a better understanding of the underlying biology of the respective tumours and lead to novel curative therapies.

Cytosine deaminase/5-fluorocytosine gene therapy and Apo2L/TRAIL cooperate to kill TRAIL-resistant tumor cells.

The death ligand Apo2L/TRAIL (Apo2 ligand/tumor necrosis factor-related apoptosis-inducing ligand) eradicates many tumor types while sparing most normal tissues. However, some tumors are resistant to TRAIL. We therefore determined if TRAIL cooperates with cytosine deaminase/5-fluorocytosine (CD/5-FC) gene therapy and investigated the mechanisms involved. Transfection of human LAN-5 neuroblastoma cells with CD rendered the cells (LAN-5-CD) sensitive to 5-FC-induced, caspase-dependent apoptosis. Mediated by caspase-3, CD/5-FC and TRAIL cooperated to induce apoptosis in these TRAIL-resistant cells and to cleave X-linked inhibitor of apoptosis protein (XIAP). In established LAN-5-CD tumors growing subcutaneously in mice, intratumorally applied TRAIL did not decrease tumor growth and systemically administered 5-FC only attenuated tumor growth. In contrast, 5-FC together with TRAIL dramatically decreased tumor growth and eradicated a tumor. Assuming sufficient gene transfer of CD in situ, CD/5-FC with TRAIL may be useful for the therapy of tumors resistant to TRAIL.

Enriching suicide gene bearing tumor cells for an increased bystander effect.

The success of cancer gene therapies requiring in vivo gene transfer is severely hampered by the low efficacy of gene transfer, which has been difficult to improve. We therefore established a novel strategy to increase the share of transduced cells post gene transfer. We hypothesized that in vivo selection of tumor cells transduced with a suicide gene effectively enriches these cells within a tumor, thus allowing for an increased bystander effect after the prodrug is given, leading to enhanced eradication of tumor cells. We reasoned that in vivo enrichment should be achieved by exploiting the metabolism of the suicide gene product. For this 'enrichment-eradication' strategy we chose a fusion gene of cytosine deaminase and uracil phosphoribosyl transferase. Positive selection (enrichment) was to be achieved by concurrently giving N-(phosphonacetyl)-L-aspartate, an inhibitor of pyrimidine de novo synthesis, which leads to pyrimidine depletion-mediated death of non-transduced cells, and cytosine, to rescue fusion gene expressing cells via the pyrimidine salvage pathway. Negative selection (eradication) was to be induced by giving the prodrug 5-fluorocytosine. Indeed, murine NXS2 neuroblastoma cells transduced with the fusion gene were effectively enriched in vitro, leading to a near-complete bystander effect. In vivo enrichment-eradication of NXS2 cells led to decreased tumor growth. This proof-of-principle study shows that enrichment-eradication may compensate the effects of low in vivo gene transfer efficacy, a major obstacle in cancer gene therapy.