Treatment exhaustion of highly active antiretroviral therapy (HAART) among individuals infected with HIV in the United Kingdon: multicentre cohort study

Objectives: To investigate whether there is evidence that an increasing proportion of HIV infected patients is starting to experience increases in viral load and decreases in CD4 cell count that are consistent with exhaustion of available treatment options. Design: Multicentre cohort study. Setting: Six large HIV treatment centres in southeast England. Participants: All individuals seen for care between 1 January 1996 and 31 December 2002. Main outcome measures: Exposure to individual antiretroviral drugs and drug classes, CD4 count, plasma HIV RNA burden. Results: Information is available on 16 593 individuals (13 378 (80.6%) male patients, 10 340 (62.3%) infected via homosexual or bisexual sex, 4426 (26.7%) infected via heterosexual sex, median age 34 years). Overall, 10 207 of the 16 593 patients (61.5%) have been exposed to any antiretroviral therapy. This proportion increased from 41.2% of patients under follow up at the end of 1996 to 71.3% of those under follow up in 2002. The median CD4 count and HIV RNA burden of patients under follow up in each year changed from 270 cells/mm3 and 4.34 log10 copies/ml in 1996 to 408 cells/mm3 and 1.89 log10 copies/ml, respectively, in 2002. By 2002, 3060 (38%) of patients who had ever been treated with antiretroviral therapy had experienced all three main classes. Of these, around one quarter had evidence of “viral load failure” with all these three classes. Patients with three class failure were more likely to have an HIV RNA burden > 2.7 log10 copies/ml and a CD4 count < 200 cells/mm3. Conclusions: The proportion of individuals with HIV infection in the United Kingdom who have been treated has increased gradually over time. A substantial proportion of these patients seem to be in danger of exhausting their options for antiretroviral treatment. New drugs with low toxicity, which are not associated with cross resistance to existing drugs, are urgently needed for such patients

TOM40 Mediates Mitochondrial Dysfunction Induced by α-Synuclein Accumulation in Parkinson's Disease.

Alpha-synuclein (α-Syn) accumulation/aggregation and mitochondrial dysfunction play prominent roles in the pathology of Parkinson's disease. We have previously shown that postmortem human dopaminergic neurons from PD brains accumulate high levels of mitochondrial DNA (mtDNA) deletions. We now addressed the question, whether alterations in a component of the mitochondrial import machinery -TOM40- might contribute to the mitochondrial dysfunction and damage in PD. For this purpose, we studied levels of TOM40, mtDNA deletions, oxidative damage, energy production, and complexes of the respiratory chain in brain homogenates as well as in single neurons, using laser-capture-microdissection in transgenic mice overexpressing human wildtype α-Syn. Additionally, we used lentivirus-mediated stereotactic delivery of a component of this import machinery into mouse brain as a novel therapeutic strategy. We report here that TOM40 is significantly reduced in the brain of PD patients and in α-Syn transgenic mice. TOM40 deficits were associated with increased mtDNA deletions and oxidative DNA damage, and with decreased energy production and altered levels of complex I proteins in α-Syn transgenic mice. Lentiviral-mediated overexpression of Tom40 in α-Syn-transgenic mice brains ameliorated energy deficits as well as oxidative burden. Our results suggest that alterations in the mitochondrial protein transport machinery might contribute to mitochondrial impairment in α-Synucleinopathies

Visualizing sound emission of elephant vocalizations: evidence for two rumble production types

Recent comparative data reveal that formant frequencies are cues to body size in animals, due to a close relationship between formant frequency spacing, vocal tract length and overall body size. Accordingly, intriguing morphological adaptations to elongate the vocal tract in order to lower formants occur in several species, with the size exaggeration hypothesis being proposed to justify most of these observations. While the elephant trunk is strongly implicated to account for the low formants of elephant rumbles, it is unknown whether elephants emit these vocalizations exclusively through the trunk, or whether the mouth is also involved in rumble production. In this study we used a sound visualization method (an acoustic camera) to record rumbles of five captive African elephants during spatial separation and subsequent bonding situations. Our results showed that the female elephants in our analysis produced two distinct types of rumble vocalizations based on vocal path differences: a nasally- and an orally-emitted rumble. Interestingly, nasal rumbles predominated during contact calling, whereas oral rumbles were mainly produced in bonding situations. In addition, nasal and oral rumbles varied considerably in their acoustic structure. In particular, the values of the first two formants reflected the estimated lengths of the vocal paths, corresponding to a vocal tract length of around 2 meters for nasal, and around 0.7 meters for oral rumbles. These results suggest that African elephants may be switching vocal paths to actively vary vocal tract length (with considerable variation in formants) according to context, and call for further research investigating the function of formant modulation in elephant vocalizations. Furthermore, by confirming the use of the elephant trunk in long distance rumble production, our findings provide an explanation for the extremely low formants in these calls, and may also indicate that formant lowering functions to increase call propagation distances in this species'

Hypermutation takes the driver’s seat

Most pediatric tumors have only very few somatic mutations. However, a recent study revealed that a subset of tumors from children with congenital biallelic deficiency of DNA mismatch repair exhibits a mutational load surpassing almost all other cancers. In these ultra-hypermutated tumors, somatic mutations in the proofreading DNA polymerases complement the congenital mismatch repair deficiency to completely abolish replication repair, thereby driving tumor development. These findings open several possibilities for exploiting ultra-hypermutation for cancer therapy

Evolutionary distances in the twilight zone -- a rational kernel approach

Phylogenetic tree reconstruction is traditionally based on multiple sequence alignments (MSAs) and heavily depends on the validity of this information bottleneck. With increasing sequence divergence, the quality of MSAs decays quickly. Alignment-free methods, on the other hand, are based on abstract string comparisons and avoid potential alignment problems. However, in general they are not biologically motivated and ignore our knowledge about the evolution of sequences. Thus, it is still a major open question how to define an evolutionary distance metric between divergent sequences that makes use of indel information and known substitution models without the need for a multiple alignment. Here we propose a new evolutionary distance metric to close this gap. It uses finite-state transducers to create a biologically motivated similarity score which models substitutions and indels, and does not depend on a multiple sequence alignment. The sequence similarity score is defined in analogy to pairwise alignments and additionally has the positive semi-definite property. We describe its derivation and show in simulation studies and real-world examples that it is more accurate in reconstructing phylogenies than competing methods. The result is a new and accurate way of determining evolutionary distances in and beyond the twilight zone of sequence alignments that is suitable for large datasets.Comment: to appear in PLoS ON

Back-reaction of Non-supersymmetric Probes: Phase Transition and Stability

We consider back-reaction by non-supersymmetric D7/anti-D7 probe branes in the Kuperstein-Sonnenschein model at finite temperature. Using the smearing technique, we obtain an analytical solution for the back-reacted background to leading order in N_f/N_c. This back-reaction explicitly breaks the conformal invariance and introduces a dimension 6 operator in the dual field theory which is an irrelevant deformation of the original conformal field theory. We further probe this back-reacted background by introducing an additional set of probe brane/anti-brane. This additional probe sector undergoes a chiral phase transition at finite temperature, which is absent when the back-reaction vanishes. We investigate the corresponding phase diagram and the thermodynamics associated with this phase transition. We also argue that additional probes do not suffer from any instability caused by the back-reaction, which suggests that this system is stable beyond the probe limit.Comment: 56 pages, 8 figures. References updated, improved discussion on dimension eight operato

A time and motion study of patients presenting at the accident and emergency department at Mater Dei Hospital

<p>Abstract</p> <p>Background</p> <p>To carry out a time and motion study of patients presenting at the Emergency Department (ED) by measuring waiting times at the ED dept throughout the day. The objectives were:</p> <p indent="1">• to determine whether waiting times are prolonged, and</p> <p indent="1">• if prolonged, at which station(s) bottlenecks occur most often in terms of duration and frequency.</p> <p>Results will be compared to the United Kingdom guidelines of stay at the emergency department.</p> <p>Methods</p> <p>A group of 11 medical students monitored all patients who attended ED between 0600 hours on the 25^thAugust and 0600 hours on the 1st September 2008. For each 24 hour period, students were assigned to the triage room and the 3 priority areas where they monitored all patient-related activity, movement and waiting times so that length of stay (LOS) could be recorded. The key data recorded included patient characteristics, waiting times at various ED process stages, tests performed, specialist consultations and follow up until admitted, discharged, or referred to another hospital area. Average waiting times were calculated for each priority area. Bottle-necks and major limiting factors were identified. Results were compared against the United Kingdom benchmarks - i.e. 1 hour until first assessment, and 4 hours before admitting/discharge.</p> <p>Results</p> <p>1779 patients presented to the ED in the week monitored. As expected, patients in the lesser priority areas (i.e. 2 & 3) waited longer before being assessed by staff. Patients requiring laboratory and imaging investigations had a prolonged length of stay, which varied depending on specific tests ordered. Specialty consultation was associated with longer waiting times. A major bottleneck identified was waiting times for inpatient admission.</p> <p>Conclusions</p> <p>In conclusion, it was found that 30.3% of priority 1 patients, 86.3% of priority 2 patients and 76.8% of priority 3 patients waited more than 1 hour for first assessment. We conclude by proposing several changes that may expedite throughput.</p

An approach for the identification of targets specific to bone metastasis using cancer genes interactome and gene ontology analysis

Metastasis is one of the most enigmatic aspects of cancer pathogenesis and is a major cause of cancer-associated mortality. Secondary bone cancer (SBC) is a complex disease caused by metastasis of tumor cells from their primary site and is characterized by intricate interplay of molecular interactions. Identification of targets for multifactorial diseases such as SBC, the most frequent complication of breast and prostate cancers, is a challenge. Towards achieving our aim of identification of targets specific to SBC, we constructed a 'Cancer Genes Network', a representative protein interactome of cancer genes. Using graph theoretical methods, we obtained a set of key genes that are relevant for generic mechanisms of cancers and have a role in biological essentiality. We also compiled a curated dataset of 391 SBC genes from published literature which serves as a basis of ontological correlates of secondary bone cancer. Building on these results, we implement a strategy based on generic cancer genes, SBC genes and gene ontology enrichment method, to obtain a set of targets that are specific to bone metastasis. Through this study, we present an approach for probing one of the major complications in cancers, namely, metastasis. The results on genes that play generic roles in cancer phenotype, obtained by network analysis of 'Cancer Genes Network', have broader implications in understanding the role of molecular regulators in mechanisms of cancers. Specifically, our study provides a set of potential targets that are of ontological and regulatory relevance to secondary bone cancer.Comment: 54 pages (19 pages main text; 11 Figures; 26 pages of supplementary information). Revised after critical reviews. Accepted for Publication in PLoS ON