Search

Background Maturation inhibitors (MIs) potently block HIV-1 maturation by inhibiting the cleavage of the capsid protein and spacer peptide 1 (CA-SP1). Bevirimat (BVM), a highly efficacious first-in-class MI against HIV-1 subtype B isolates, elicited sub-optimal efficacy in clinical trials due to polymorphisms in the CA-SP1 region of the Gag protein (SP1:V7A). HIV-1 subtype C inherently contains this polymorphism thus conferring BVM resistance, however it displayed sensitivity to second generation BVM analogs. Results In this study, we have assessed the efficacy of three novel second-generation MIs (BVM analogs: CV-8611, CV-8612, CV-8613) against HIV-1 subtype B and C isolates. The BVM analogs were potent inhibitors of both HIV-1 subtype B (NL4-3) and subtype C (K3016) viruses. Serial passaging of the subtype C, K3016 virus strain in the presence of BVM analogs led to identification of two mutant viruses—Gag SP1:A1V and CA:I201V. While the SP1:A1V mutant was resistant to the MIs, the CA:I120V mutant displayed partial resistance and a MI-dependent phenotype. Further analysis of the activity of the BVM analogs against two additional HIV-1 subtype C strains, IndieC1 and ZM247 revealed that they had reduced sensitivity as compared to K3016. Sequence analysis of the three viruses identified two polymorphisms at SP1 residues 9 and 10 (K3016: N9, G10; IndieC1/ZM247: S9, T10). The N9S and S9N mutants had no change in MI-sensitivity. On the other hand, replacing glycine at residue 10 with threonine in K3016 reduced its MI sensitivity whereas introducing glycine at SP1 10 in place of threonine in IndieC1 and ZM247 significantly enhanced their MI sensitivity. Thus, the specific glycine residue 10 of SP1 in the HIV-1 subtype C viruses determined sensitivity towards BVM analogs. Conclusions We have identified an association of a specific glycine at position 10 of Gag-SP1 with an MI susceptible phenotype of HIV-1 subtype C viruses. Our findings have highlighted that HIV-1 subtype C viruses, which were inherently resistant to BVM, may also be similarly predisposed to exhibit a significant degree of resistance to second-generation BVM analogs. Our work has strongly suggested that genetic differences between HIV-1 subtypes may produce variable MI sensitivity that needs to be considered in the development of novel, potent, broadly-active MIs. Graphic abstract

Suites of concepts and approaches have been launched during recent years to promote urban nature and greener cities. However, it is doubtable whether tinkering within the current economic and political system can provide adequate solutions. Nature-based Solutions can be seen as a new conceptual approach to the human-ecological connection, and as an outcome of an evolutionary development of socio-ecological concepts. In this Communication, we argue for drawing upinspiration by natureas an outset for the development of more sustainable and inclusive cities, balancing anthropocentric and ecocentric values and acknowledging the importance of the social and governance dimensions in a more balanced socio-ecological perspective. We call this approach Nature-based Thinking.

Die schnelle Einleitung einer Therapie ist fur die Prognose von akuten Schlaganfallpatienten entscheidend. Dies erfordert ein optimiertes Management der Patienten nicht nur im Krankenhaus, sondern auch im prahospitalen Ablauf. Die Bedeutung des Notarztes ist in diesem Kontext nicht gesichert und es stellt sich die Frage, ob die Anwesenheit des Notarztes einen positiven Einfluss auf das prahospitale und hospitale Management von Schlaganfallpatienten hat, oder ob die Nachforderung eines Notarztes die Behandlungsinitiierung verzogert. Zur Untersuchung dieser Frage analysierten die Autoren retrospektiv alle thrombolysierten Patienten des Universitatsklinikums Jena in den Jahren 2009 bis einschlieslich 2015 im Hinblick auf Unterschiede im Akutmanagement in Abhangigkeit davon, ob sie mit oder ohne Notarztbegleitung die Klinik erreichten. Hauptergebnis der Untersuchung ist, dass vom Notarzt begleitete Patienten, verglichen mit Patienten, die ohne Notarztbegleitung die Klinik erreichten, eine signifikant schnellere Behandlung mit rtPA erhielten (p = 0,007). Die Uberlegenheit der notarztlich begleiteten Patienten blieb auch dann noch bestehen, wenn die schnellere Ankunftszeit der Patienten ohne Notarztbegleitung eingerechnet wurde. Die Analyse verschiedener Einflussfaktoren konnte diesen Unterschied nicht erklaren. Die Vermutung, dass ein schnelleres prahospitales Management unter Ausschluss des Notarztes auch zu einer schnelleren Behandlungsinitiierung fuhrt, kann nicht bestatigt werden. Ob die Anwesenheit des Notarztes auch auserhalb der lokalen Gegebenheiten der vorliegenden Studie einen positiven Einfluss auf das intrahospitale Schlaganfallmanagement hat, sollte in einer prospektiven Studie weiter untersucht werden.

Mutational inactivation of ATRX (α-thalassemia mental retardation X-linked) represents a defining molecular alteration in large subsets of malignant glioma. Yet the pathogenic consequences of ATRX deficiency remain unclear, as do tractable mechanisms for its therapeutic targeting. Here we report that ATRX loss in isogenic glioma model systems induces replication stress and DNA damage by way of G-quadruplex (G4) DNA secondary structure. Moreover, these effects are associated with the acquisition of disease-relevant copy number alterations over time. We then demonstrate, both in vitro and in vivo, that ATRX deficiency selectively enhances DNA damage and cell death following chemical G4 stabilization. Finally, we show that G4 stabilization synergizes with other DNA-damaging therapies, including ionizing radiation, in the ATRX-deficient context. Our findings reveal novel pathogenic mechanisms driven by ATRX deficiency in glioma, while also pointing to tangible strategies for drug development., ATRX deficiency is linked to genomic stability in cancer cells. Here, the authors show that ATRX inactivation induces G-quadruplex formation, leading to genome-wide DNA damage, and the use of G-quadruplex stabilisers can be exploited therapeutically in ATRX deficient gliomas.

BACKGROUND One of the most significant, and growing, challenges in modern medicine, i.e. the treatment of chronic wounds, is marked by nonuniform data. This concerns both prevalence and incidence of chronic dermatosis, in particular venous ulcers (ulcus cruris), as well as the impact on the health-related quality of life, and practical and economic parameters of the success of different therapies. PURPOSE The aim of this work is to examine the epidemiology of chronic wounds, in particular age-associated venous ulcers, their impact on health-related quality of life, the treatment regimen, and practical and economic parameters of the success of different therapies. MATERIALS AND METHODS Performed were analysis of data on the care of venous ulcers in Germany, based on secondary data of Barmer GEK from 2009 and 2012, comparison with data of a NHS Kent Community Health Trust study, and analysis of studies concerning structures, processes and critical success factors for the treatment of chronic wounds, including economic effects. CONCLUSION Early causal therapy with treatment based on the stage of the wound, consequent goal-oriented interdisciplinary care, and relapse prophylaxis is critical for successful healing of venous ulcers. The costs of treatment significantly correlate with the duration of treatment which can be reduced by up to 60% using guideline-based concepts for the treatment of chronic wounds. Treatment success, in particular with regard to cost-benefit considerations, can be optimized by telemedicine networks of key players who treat chronic wounds.

More than 1.5 million people were diagnosed with skin cancer in 2012 in Germany-of which 318,000 were malignant melanoma. The number of malignant skin tumours has increased by 60% since 2005. Epithelial skin cancers are even more common. Since 2012, 1.3 million diagnoses have been documented. This incidence represents an increase of 79% within 7 years. The number of skin cancer patients treated in German hospitals has also increased. In 2014, 99,613 patients were treated as inpatients with the diagnosis of skin cancer; in 2000 there were 57,147 patients. This was the largest growth rate among all cancer treatments in hospitalised patients. The continuously changing age pyramid leads to an expected further growth of the incidence of skin tumours. In parallel the development of molecular knowledge in tumorigenesis is also rapid. A series of cell-specific mutations have been described in recent years for various skin tumours. Mutations are found mainly in genes engaging their translation products at key positions in regulatory cell metabolism or cell division. These include oncogenes, which have greatly increased activity due to targeted mutations or tumor suppressor genes and act under physiological conditions as negative regulators that are inactivated by mutations. These findings have led to the development of a series of new promising compounds for the treatment of skin tumours.

Neoadjuvant therapy increases rates of margin-negative resection of borderline resectable pancreatic ductal adenocarcinoma (BL-PDAC). Criteria for BL-PDAC resection following neoadjuvant chemotherapy and radiation therapy (NCRT) have not been clearly defined.Fifty consecutive patients with BL-PDAC who received NCRT from 2007 to 2012 were identified. Computed tomography (CT) scans pre- and post-treatment were centrally reviewed.Twenty-nine patients (58 %) underwent resection following NCRT, while 21 (42 %) remained unresected. Patients selected for and successfully undergoing resection were more likely to have better performance status and absence of the following features on pre- and post-treatment CT: superior mesenteric vein/portal vein encasement, superior mesenteric artery involvement, tumor involvement of two or more vessels, and questionable/overt metastases (allApparent radiographic extent of vascular involvement does not change significantly after NCRT. Patients without metastatic disease should be chosen for surgical exploration based on adequate performance status and lack of disease progression.

Antiretroviral therapy has led to a profound improvement in the clinical care of HIV-infected patients. However, drug tolerability and the evolution of drug resistance have limited treatment options for many patients. Maturation inhibitors are a new class of antiretroviral agents for treatment of HIV-1. They act by interfering with the maturation of the virus by blocking the last step in Gag processing: the cleavage of the capsid-spacer peptide 1 (CA-SP1) intermediate to mature CA by the viral protease (PR). The first-in-class maturation inhibitor bevirimat (BVM) failed against a subset of HIV-1 isolates in clinical trials due to polymorphisms present in the CA-SP1 region of the Gag protein. Sequence analysis indicated that these polymorphisms are more common in non-clade B strains of HIV-1 such as HIV-1 clade C. Indeed, BVM was found to be ineffective against HIV-1 clade C molecular clones tested in this study. A number of BVM analogs were synthesized by chemical modifications at the C-28 position to improve its activity. The new BVM analogs displayed potent activity against HIV-1 clade B and C and also reduced infectivity of the virus. This study identifies novel and broadly active BVM analogs that may ultimately demonstrate efficacy in the clinic.

Obwohl Richtlinien fur die Behandlung von unterschiedlichen Atiologien (Dekubitus, Ulcus cruris, Diabetisches Fussyndrom etc.) und Pflegestandards bei Patienten mit chronischen Wunden bereits publiziert wurden, kann ein Grosteil der Patienten davon nicht profitieren. Anhand einer 83-jahrigen Patientin werden stellvertretend fur eine Vielzahl von, vor allem geriatrischen, Patienten die existierenden Defizite auch aus der Sicht der Angehorigen dargestellt und analysiert. Es wird versucht Losungsmoglichkeiten und Erfahrungen aufzuzeigen, um diesen Patienten eine adequate und effiziente Behandlung zukommen zu lassen. Die Kalkulationen aus internationalen Analysen, aber auch die Analysen aus eigenen laufenden Projekten belegen ein betrachtliches Einsparungspotential fur die Kostentrager bei gleichzeitig qualitativ und quantitative besserem Behandlungserfolg.

BACKGROUND: Pressure ulcers, ulcus cruris and surgical wound infections and disorders belong to the most frequent diseases in our medical system. Treatment of such chronic wounds is often troubled due to subjective documentation, which is usually imprecise. Judging slight changes of lesions is often almost impossible, even for experienced health professionals. Existing computer-based documentation tools allow only measurement of wound size and are actually impractical and not cost effective. METHODS: We have developed a new, computer-based, easy-to-use wound analysing tool by using a "no-touch technique". This semiautomatic software can exactly measure the size of a lesion, including vertical and horizontal diameter, area and circumference, by analysing a picture taken by a digital camera. To straighten out the photo, a calibration marker is placed next to the wound which optimizes the quality of the analysis. Furthermore, the system is capable of tissue validation. Necrosis, fibrin and granulation tissue are automatically distinguished and quantified, which is essential for judging the wound-healing process. After finishing the analysis, a report is created and saved in a database together with all the collected data and pictures. RESULTS: Histological samples of chronic wounds have been taken and surveyed which the have approved the validity of the analyses. Additionally, several independant observers have demonstrated the efficacy of the system by analysing the same lesion. Measuring the size and the tissue types of a wound takes about 90 seconds per lesion. Creating a report with suggestions for therapy needs 4 min. CONCLUSIONS: Our newly developed tool is easy to use, accurate and cheap. The software runs on common PCs and the pictures can be taken by an ordinary state-of-the-art digital camera. With this tool swift analyses of wounds can be performed, objectively stating the size and the tissue composition of the lesions, which is impossible for the naked human eye.

Grundlagen: Patienten mit therapierefraktarer Angina pectoris waren bislang nicht mit konventionellen Methoden behandelbar. Die Transmyokardiale Laserrevaskularisation (TMR) stellt eine therapeutische Option dar. Das Ziel dieser Studie war es, die Sicherheit und die klinische Effektivitat der TMR zu evaluieren. Methodik: Die TMR wurde bei 40 Patienten unter erstmaliger Verwendung eines neuen Holmium: YAG-Lasers durchgefuhrt. Davon wurden 24 Patienten, die in 96 % mindestens eine vorangegangene Bypassoperation (ACBP) aufwiesen, nur mit einer TMR behandelt. Im Durchschnitt wurden 24 Kanale angelegt. 16 Patienten erhielten eine Kombination mit einer herkommlichen Bypassoperation, wobei 25 % der Patienten bereits eine fruhere Bypassoperation hatten. Bei diesen Patienten wurden im Durchschnitt 17,3 Kanale angelegt. Ergebnisse: Bei allen Patienten kam es zu einer signifikanten Verbesserung der AP-Symptomatik um 2 CCS-Klassen (Canadian Cardiovascular Society) und einer Verbesserung der Leistungsfahigkeit in der Fahrradergometrie um 21 %. Ein Unterschied hinsichtlich dieser Parameter war zwischen der TMR und der TMR+CABG nicht festzustellen. Perioperativ verstarb 1 Patient an einem Myokardinfarkt (nur TMR). Sonstige Komplikationen waren Wundinfektionen (n=7,5 %) und Pneumonien (n=5 %). Schlusfolgerungen: Diese Studie zeigt, das die TMR mit einem neuen Holmium: YAG-Laser eine sichere und effektive Methode mit einer geringen perioperativen Mortalitat ist. Sie fuhrt zu einer Reduktion der Angina pectoris und zur Verbesserung der Lebensqualitat bei Patienten mit schwerer diffuser Koronarsklerose.

We report a case of idiopathic hypertrophic cranial pachymeningitis (IHCP) associated with an orbital pseudotumor and granulocytic thyroiditis of unknown origin. The patient suffered from progressive and finally complete loss of visual acuity, as well as from multiple cranial nerve dysfunctions. Medical treatment and radiation therapy were not beneficial. As reported in the literature, the CT and MRI findings of IHCP were non-specific; thus, diagnosis had to be made by exclusion and open biopsy was required. An inflammatory pseudotumor of the orbit is rarely found in patients with IHCP. Thyroiditis has not yet been reported in the context of IHCP. The patient also suffered from anosmia, which is an unusual feature of IHCP.

This study demonstrates the feasibility of expressing recombinant genes (Bax) in anin vivo liposome-mediated gene transfer approach. Furthermore, Bax overexpression has shown to contribute in the increase of cell death thus revealing the attractiveness for further research using Bax and refined protocols. Liposome-mediated gene transfer exhibited no toxis side effectsin vivo, in mice with only liposome administration, thereby further enhancing the positivity of liposomes.

The Tigalak intrusion is a dominantly dioritic layered body, about 80 km2 in area, which ranges in composition from norite to granodiorite. Local areas of the layered rocks display upward fractionation from norite to ferrodiorite. Periodic reversals of mineral composition trends record the emplacement of less fractionated dioritic magma. Heterogeneous mixtures of dioritic and granodioritic rocks occur widely in mappable lenses and layers that alternate up section and along the strike with more uniformly layered rocks. In these mixtures, chilled dioritic pillows occur abundantly in a hybrid cumulate matrix of granodiorite to diorite composition. Cross-cutting granodioritic dikes grade upward into stratigraphically-bound lensoid masses of the hybrid cumulates. It appears that the hybrid rocks formed as a result of the emplacement of the granodioritic magma through lower cumulates into the dioritic magma chamber and that the dioritic pillows represent chilled bodies of Ferich dioritic magma that commingled with cooler granodioritic magma and settled to the floor of the Tigalak magma chamber.

A New Limit to the Galactic Magnetic Field Set by Measurements of the Zeeman Splitting of the Hydrogen Line

A new and successful attempt to measure magnetic fields in the Milky Way using the 250-ft radio telescope at Jodrell Bank is reported. The measurements were made by observing the Zeeman splitting of the neutral hydrogen line profiles. The strongest indication of Zeeman splitting was shown by the narrow deep feature of Taurus A. This feature has been shown to be double and has been resolved into two absorbing clouds, one having a magnetic field of 2.5 x 10/sup -5/ gauss and the other a magnetic field of 5 x 10/sup -6/ gauss. Similar but weaker Zeeman features were found in the absorption spectra of Cassiopeia A and Cygnus A. The maximum components of the magnetic field seen in the clouds of the Cassiopeia A and Cygnus A directions are about 5 x 10/sup -6/ gauss. Therefore, these results suggest that the general galactic magnetic field is of the order of 5 x 10/sup -6/ gauss. (L.T.W.)