Structural Aspects of Drug Resistance and Inhibition of HIV-1 Reverse Transcriptase

HIV-1 Reverse Transcriptase (HIV-1 RT) has been the target of numerous approved anti-AIDS drugs that are key components of Highly Active Anti-Retroviral Therapies (HAART). It remains the target of extensive structural studies that continue unabated for almost twenty years. The crystal structures of wild-type or drug-resistant mutant HIV RTs in the unliganded form or in complex with substrates and/or drugs have offered valuable glimpses into the enzyme’s folding and its interactions with DNA and dNTP substrates, as well as with nucleos(t)ide reverse transcriptase inhibitor (NRTI) and non-nucleoside reverse transcriptase inhibitor (NNRTIs) drugs. These studies have been used to interpret a large body of biochemical results and have paved the way for innovative biochemical experiments designed to elucidate the mechanisms of catalysis and drug inhibition of polymerase and RNase H functions of RT. In turn, the combined use of structural biology and biochemical approaches has led to the discovery of novel mechanisms of drug resistance and has contributed to the design of new drugs with improved potency and ability to suppress multi-drug resistant strains

Improving palliative care outcomes for Aboriginal Australians: Service providers' perspectives

Background: Aboriginal Australians have a lower rate of utilisation of palliative care services than the general population. This study aimed to explore care providers’ experiences and concerns in providing palliative care for Aboriginal people, and to identify opportunities for overcoming gaps in understanding between them and their Aboriginal patients and families. Methods: In-depth, qualitative interviews with urban, rural and remote palliative care providers were undertaken in inpatient and community settings in Western Australia. Interviews were audio-recorded, transcribed verbatim and coded independently by two researchers with QSR NVivo 10 software used to help manage data. Data analysis was informed by multiple theoretical standpoints, including the social ecological model, critical cultural theories and the ‘cultural security’ framework. Thematic analysis was carried out that identified patterns within data. Results: Fifteen palliative care providers were interviewed. Overall they reported lack of understanding of Aboriginal culture and being uncertain of the needs and priorities of Aboriginal people during end-of-life care. According to several participants, very few Aboriginal people had an understanding of palliative care. Managing issues such as anger, denial, the need for non-medical support due to socioeconomic disadvantage, and dealing with crises and conflicts over funeral arrangements were reported as some of the tensions between Aboriginal patients and families and the service providers.Conclusion: Early referral to palliative care is important in demonstrating and maintaining a caring therapeutic relationship. Paramount to meeting the needs for Aboriginal patients was access to appropriate information and logistical, psychological and emotional support. These were often seen as essential but additional to standard palliative care services. The broader context of Aboriginal history and historical distrust of mainstream services was seen to impinge on Aboriginal people’s willingness and ability to accept care and support from these services. This context needs to be understood and acknowledged at the system level. More cultural safety training was requested by care providers but it was not seen as replacing the need for an Aboriginal worker in the palliative care team

Oral Ondansetron Administration in Emergency Departments to Children with Gastroenteritis: An Economic Analysis

Stephen Freedman and colleagues performed a cost analysis of the routine administration of ondansetron in both the United States and Canada and show that its routine administration to eligible children in such settings could provide substantial benefit

Dental therapy before and after radiotherapy–an evaluation on patients with head and neck malignancies

The present investigation evaluates the dental care situation of patients with head and neck cancer before and after radiotherapy. The situations of these patients in 1993 and 2005 were compared to detect similarities, differences and developments. In the years 1993 and 2005, 37 and 36 patients, respectively, with head and neck cancer treated by the local departments of otorhinolaryngology and of radiotherapy were examined consecutively according to their aftercare appointments. Time points of radiotherapy treatment of the patients evaluated in 1993 varied from 1984 to 1993. The patients evaluated in 2005 had received radiotherapy between 1998 and 2005. Therefore the applied radiotherapeutic regimen differed not only between the two groups of patients, but also within each group. The information for these investigations was provided anonymously. It was evaluated with descriptive statistics. The evaluation of the data shows distinct differences with respect to preventive and therapeutic dental care measures. In 2005, 35 out of 36 patients (97.2%) had a dental consultation before radiotherapy (1993, 65%). All 27 dentate patients (100%) obtained a splint for fluoride application (1993, none). 29% fewer edentulous patients were seen than in 1993. The number of teeth destroyed decreased from 19.2% (1993) to 7.8% in 2005. Mycoses due to Candida spp. and chronic failures in wound healing were rare (5.5%). In the course of the 12 years, prophylactic measures, such as the application of splints for fluoride treatment, were intensified. However, concepts for the dental care of patients undergoing radiotherapy, especially following the radiation, should be widened to avoid ruined teeth and long delayed wound healings

Susceptibility of the human retrovirus XMRV to antiretroviral inhibitors

<p>Abstract</p> <p>Background</p> <p>XMRV (xenotropic murine leukemia virus-related virus) is the first known example of an exogenous gammaretrovirus that can infect humans. A limited number of reports suggest that XMRV is intrinsically resistant to many of the antiretroviral drugs used to treat HIV-1 infection, but is sensitive to a small subset of these inhibitors. In the present study, we used a novel marker transfer assay to directly compare the antiviral drug sensitivities of XMRV and HIV-1 under identical conditions in the same host cell type.</p> <p>Results</p> <p>We extend the findings of previous studies by showing that, in addition to AZT and tenofovir, XMRV and HIV-1 are equally sensitive to AZddA (3'-azido-2',3'-dideoxyadenosine), AZddG (3'-azido-2',3'-dideoxyguanosine) and adefovir. These results indicate that specific 3'-azido or acyclic nucleoside analog inhibitors of HIV-1 reverse transcriptase (RT) also block XMRV infection with comparable efficacy <it>in vitro</it>. Our data confirm that XMRV is highly resistant to the non-nucleoside RT inhibitors nevirapine and efavirenz and to inhibitors of HIV-1 protease. In addition, we show that the integrase inhibitors raltegravir and elvitegravir are active against XMRV, with EC₅₀values in the nanomolar range.</p> <p>Conclusions</p> <p>Our analysis demonstrates that XMRV exhibits a distinct pattern of nucleoside analog susceptibility that correlates with the structure of the pseudosugar moiety and that XMRV is sensitive to a broader range of antiretroviral drugs than has previously been reported. We suggest that the divergent drug sensitivity profiles of XMRV and HIV-1 are partially explained by specific amino acid differences in their respective protease, RT and integrase sequences. Our data provide a basis for choosing specific antiretroviral drugs for clinical studies in XMRV-infected patients.</p

Multistrange baryon production in Au-Au collisions at root s(NN)=130 GeV

The transverse mass spectra and midrapidity yields for Xis and Omegas are presented. For the 10% most central collisions, the (Xi) over bar (+)/h(-) ratio increases from the Super Proton Synchrotron to the Relativistic Heavy Ion Collider energies while the Xi(-)/h(-) stays approximately constant. A hydrodynamically inspired model fit to the Xi spectra, which assumes a thermalized source, seems to indicate that these multistrange particles experience a significant transverse flow effect, but are emitted when the system is hotter and the flow is smaller than values obtained from a combined fit to pi, K, p, and Lambdas